Victoria M Villaflor, Ravi Salgia
Department of Medicine, Section of Hematology/Oncology University of Chicago, Chicago, IL, USA
| Date of Submission | 27-Mar-2012 |
| Date of Acceptance | 10-Jan-2013 |
| Date of Web Publication | 19-Mar-2013 |
Correspondence Address:
Victoria M Villaflor
Department of Medicine, Section of Hematology/Oncology University of Chicago, Chicago, IL
USA
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/1477-3163.109253
Abstract
Lung cancer is a heterogeneous group of diseases. There has been much research in lung cancer over the past decade which has advanced our ability to treat these patients with a more personalized approach. The scope of this paper is to review the literature and give a broad understanding of the current molecular targets for which we currently have therapies as well as other targets for which we may soon have therapies. Additionally, we will cover some of the issues of resistance with these targeted therapies. The molecular targets we intend to discuss are epidermal growth factor receptor (EGFR), Vascular endothelial growth factor (VEGF), anaplastic large-cell lymphoma kinase (ALK), KRAS, C-MET/RON, PIK3CA. ROS-1, RET Fibroblast growth factor receptor (FGFR). Ephrins and their receptors, BRAF, and immunotherapies/vaccines. This manuscript only summarizes the work which has been done to date and in no way is meant to be comprehensive.
Keywords: Cellular mechanism, HGF, MET, oncogene, receptor tyrosine kinase, targeted cancer therapy
Introduction
Lung cancer is a world-wide problem. In the United States, there are approximately 226,000 new cases annually with an estimated 160,000 deaths. [1] It is the largest cause of cancer deaths in the United States. Survival rates have improved slightly since the 1990’s. [2] However, most patients still present with inoperable disease. Until the last decade, we have treated this disease with a “one size fits all approach.” Early data in the treatment of metastatic non-small lung cancer (NSCLC) suggested that all platinum-containing doublets were equally efficacy ious in prolonging progression-free survival (PFS) and overall survival (OS). [3] More recent findings have suggested that histology plays a role in the treatment outcome. Scagliotti et al., data were notable for a slight improvement in OS and PFS with platinum and pemetrexed for non-squamous histology whereas, platinum and gemcitabine had a slight advantage in squamous cell histology. [4] Additionally, there has been a small subset of patients who respond to the newer targeted agents as was initially seen with the drug gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). [5] There are many more targets that are being discovered and studied, some which may play a role in the treatment of this dread disease.
To date, there have been multiple driver oncogenes described predominantly in adenocarcinoma of the lung of those who were never or light smokers. These include, EGFR, anaplastic large-cell lymphoma kinase (ALK), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS), MET – is a proto-oncogene that encodes a protein known as hepatocyte growth factor receptor, Recepteur d’Origine Nantais (RON), ROS1 a newly exploved chromosome translocation, Ephrin type-B receptor -4(EPHB4), Ephrin type-A receptor -2(EPHA 2). In squamous cell carcinoma of the lung, Phosphatidylinositide 3-kinases (PI3K) and Fibroblast growth factor receptor ( FGFR) alterations have been identified. This is an exciting time in non-small cell lung cancer treatment as the development of targeted therapy has afforded us a more personalized approach. We have clinically effective therapies for patients with NSCLC whose tumors harbor EGFR mutations, ALK rearrangements, and ROS-1 rearrangements which may result in survival prolongation. [6],[7],[8],[9],[10],[11]
Despite these advances, we still have a long way to go to better treat our patients. The scope of this paper is to describe the targets for which there are therapies or resistance is an issue. Additionally, we will describe some of the newer targets and immune therapies under investigation.
Epidermal Growth Factor Receptor
Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), is involved with cell differentiation, proliferation, angiogenesis, and apoptosis. Initial responses to EGFR TKI were seen in a non-selective Japanese population with gefitinib. [12] Following an open access trial where all patients with NSCLC were treated with gefitinib, the clinical characteristics of these patients noted to respond were described as Asian females with adenocarcinoma (bronchoalveolar carcinoma), and were non-smoking or light smokers. [13] It was not until the work of Lynch and Paez, that the EGFR molecular mutations that were targeted were described. [14],[15] Currently, patients are routinely tested for EGFR mutations and recent trials have demonstrated that patients harboring activating mutations for EGFR, with metastatic lung cancer, should receive an EGFR-TKI as initial treatment. [9],[16],[17] We also have evaluated EGFR-TKI’s with the addition of chemotherapy that has not been successful to date. [18],[19] Patients harboring EGFR mutations initially respond well to EGFR-TKI’s however, acquired mutations do occur while on therapy which can render the patient resistant to the available drugs. These mutations include EGFR T790M point mutation. The strategies currently in development to overcome resistance include the use of oral irreversible, small molecules or Human Epidermal Growth Factor Receptor and pan-human epidermal receptor (pan-HER) inhibitors. These drugs include afatinib, neratinib, pelitinib, (Astra Zeneca) AZD8931, canertinib and (Pfizer) PF299. [20] Studies are ongoing to evaluate these drugs in patients with acquired resistance to EGFR inhibition. MET upregulation can also account for acquired resistance in these patients. Studies directed at inhibiting MET along with continued EGFR-TKI therapy are being carried out to evaluate overcoming acquired resistance. Drugs in development targeting C-met include ARQ197 (ArQule) a TKI and Met MAb (Onartuzumab) a monoclonal antibody. [20]
Anaplastic Large-Cell Lymphoma Kinase
Anaplastic large-cell lymphoma kinase (ALK) is a more recent target of a RTK which is promising in NSCLC. It is in the insulin receptor superfamily and its precise function is not well understood. Activating mutations or translocations of ALK have been found in a few different types of malignancies and most notably, initially found in lymphoma for which it was named. In NSCLC, echinoderm microtubule-associated protein-like 4 EML4-ALK is the most common of a group of aberrant fusion genes occurring in 2-7% of patients typically found in never or light smokers. [7] Patients that harbor a mutation are often susceptible to targeted kinase inhibition with crizotinib. [7] This compound recently received FDA approval for use in patients harboring ALK mutation with NSCLC. Resistance to this compound develops over time and the mechanism is unclear. Currently, heat shock protein- 90 (HSP-90) has been identified as a potential target for crizotinib resistance and is being evaluated for patients who become resistant to crizotinib. Ganetespib has demonstrated some activity in EML-4ALK-mutated patients and is currently in study. There is much work to be done to evaluate the mechanisms of resistance to better target this group of patients.
Kirsten Rat Sarcoma Viral Oneogene Hoholog (KRAS)
In NSCLC, KRAS mutations occur predominately at codon 12 or 13 most often in patients with a history of tobacco use. [21],[22] Mutations are responsible for KRAS activation which commonly occurs in NSCLC. This is most common in patients with adenocarcinoma (30%), although approximately, 5% of patients with squamous cell carcinoma may have activation. [23],[24] KRAS mutations in NSCLC patients are believed to be a negative prognostic indicator but, this too is controversial. [25],[26] Studies which evaluated the use of EGFR inhibition both by monoclonal antibody as well as TKIs failed to demonstrate a difference between KRAS mutants and an unselected population of NSCLC for response rates, overall survival (OS), and progression free survival PFS when EGFR inhibition was used. [27],[28],[29],[30]
Understanding of the clinical implications and biologic role of KRAS mutations in NSCLC has remained elusive. [24] It is believed that rat sarcoma RAS proteins function as guanosine diphosphate/guanosine triphosphate-regulated binary on-off switches. RAS mutants tip the regulated switch to on, leading to independent and persistent activation of the signaling pathway Raf-MEK-ERK cascade. This cascade is associated with proliferation, metastasis, and survival of the malignant cell. [31],[32],[33],[34] Additionally, recent studies have also demonstrated that RAS uses additional effectors to promote tumorigenesis including BRAF and Phosphatidylinositol 3-kinase catalytic subunit PIK3CA. [35] Currently, there are no targeted agents that have proven to be efficacious in the KRAS mutation population. In NSCLC the response rates to EGFR inhibition with monoclonal antibody is the same with or without KRAS mutations, unlike the findings in colorectal cancer. [36],[37],[38] There are no direct inhibitors of KRAS, but, it appears there may be potential targets which function downstream of RAS. These include the RAS/RAF/MEK pathway. This pathway includes many proteins including mitogen-activated protein kinases which was originally called extracellular – signal – regulated kinases (ERK). This pathway acts as an on / off switch by adding phosphate groups to neighboring proteins. Sorafenib is a weak inhibitor of proto-oncogene RAF but, MEK appears more promising. [39],[40],[41] The BATTLE trial initially demonstrated a benefit with sorafenib in KRAS-mutated NSCLC patients, however, this did not ultimately prove out. [42] There are however, multiple inhibitors of BRAF GlaxoSmithKline (GSK2118436) and MEK (selumetinib) under investigation in this population.
C-MET/RON
MET is part of the RTK family. It is a proto-oncogene which encodes for the protein hepatocyte growth factor receptor. Its natural ligand is hepatocyte growth factor and scatter factor. MET’s role in carcinogenesis is activation of oncogenic pathways such as RAS, PI3K, Signal transducer and activator of transcription 3 (STAT-3), and Beta-catenin, angiogenesis, and metastasis. [29] MET can be activated by mutations, autocrine/paracrine growth, overexpression by gene amplification, or decreased degradation. [43] MET gene mutations and amplification has been reported at low frequency, but as predictors of therapeutic sensitivity. [44] Studies have suggested that approximately 40% of lung cancer tissue overexpresses MET. [45] Amplification have been described in EGFR resistance and studies are ongoing to overcome EGFR resistance with addition of MET inhibition. [46] Clinical studies are ongoing evaluating Foretinib (multikinase Met Inhibitor), MetMAb (single-arm humanized anti-Met antibody), Exelixis compound XL-184 [Kinase inhibitor of MET, vascular endothelial growth factor receptor 2 (VEGFR2) and rearranged during transfection, (RET)], ficlatuzumab, and preclinical studies with MedKoo Biosciences/Pfizer compound PHA665752. All of these clinical trials are evaluating MET inhibition in EGFR-acquired resistance. [43]
RON is a MET-related RTK. Macrophage stimulating protein is its natural ligand. Beta-1-integrins can also activate RON via c-Src-dependant signaling pathways. [47] RON is localized to chromosome band 3p21.3, a region known for tumor suppressor function and loss of heterozygosity. [48],[49] Its role is regulation of inflammation and contributes to growth and metastasis. Ron signaling has a major effect on the motility and activation of macrophages. In lung cancer, however, the role is very synergistic or additive with MET which promotes transformation, cell spreading, and motility as well as promotes survival, [50] and [51] MET and RON are both implicated in tumor progression and development of metastasis. [52],[53],[54] methylgene incorporated compound MGCD265 is a multikinase inhibitor directed against c-MET, VEGR1, 2, 3, RON, and Tie-2, and is currently in early clinical trials.
PIK3CA
Phosphatidylinositol-3-kinase p110 alpha catalytic subunit isoform (PIK3CA) amplification, and to a lesser extent, mutations are seen in NSCLC. [55],[56],[57] PIK3CA mutations and amplification may be involved in EGFR resistance. [58] protein kinase B/mammalian target of rapamycin PI3K/AKT/mTOR pathway is activated in early stages of development of lung cancer. [59] AKT regulates cell survival in tumors and has been implicated in the oncogenesis and progression of lung cancer. [60] PI3K is activated by EGFR stimulation which subsequently activates AKT. Activation of PI3K and AKT signaling occurs with somatic mutations of PIK3CA clustering in exons 9 and 20. [60],[61] PIK3CA amplification has been reported in approximately 15% of patients with NSCLC. [56],[57],[62] These mutations and amplifications appeared to be associated with poor survival and resistance to treatment with EGFR TKI’s. [60],[63]
Drugs which appear to interfere with this pathway include inhibitors of mTOR, AKT, and P13K. Currently, many of these targeted agents are under development in the treatment of NSCLC both with and without the use of cytotoxics. PI3K inhibitors include Novartis Pharmaceuticals BKM120, Genentech and Exelixis GDC0941, and XL-147, respectively. AKT inhibitors include Merck MK 2206. mTOR inhibitors include sirolimus, everolimus and temsirolimus. Of note, Novartis BEZ235 is a dual PI3K and mTOR inhibitor which appears promising in early clinical development. [64],[65]
Ros1
Ros1 is a newly explored chromosomal translocation and is a member of the RTK of the insulin receptor family in lung cancer although it has been described in other tumors. [66] As this is a new target, little is known about tumors which possess this translocation. A recent study demonstrated approximately 2% of patients possess this translocation and the patients typically have a similar profile to patients with EML4-ALK translocation. [66] The study also demonstrated cell-line sensitivity to crizotinib. [66] Patients with ROS1 translocation were enrolled into an expansion access cohort of an early phase of crizotinib development with promising results. [7],[66]
RET/RET Fusion
RET has been described in multiple endocrine neoplasia type 2 (MEN 2) syndrome and sporadic medullary thyroid cancer. [67] RET is involved with cell proliferation, neuronal navigation, cell migration, and cell differentiation. [68] More recently, a novel gene fusion involving RET tyrosine kinase and either KIF5B or CCDC6 was reported in lung adenocarcinomas which is similar to those translocations found in thyroid cancers. [69],[70],[71],[72] The patients who seemed to have these translocations tended to be younger in age, never-smokers, had early lymph-node metastases, poor differentiation, and a solid-predominant subtype. [73] The RET fusion gene was evaluated in 936 patients with surgically resected NSCLC and found to occur in 1.4% of NSCLC and 1.7% of lung adenocarcinomas. [73] This may prove to be an important target for patients with NSCLC as clinically available TKI’s such as sunitinib, sorafenib, and vandetanib are commercially available. [74] Cells expressing Kinesin heavy chain isoform 5A -RET protoncogene KIF5B-RET were noted to be sensitive to multitargeted kinase inhibitors that inhibit RET. [73] Additionally, these drugs have been shown to target RET kinase and have shown activity in patients with thyroid cancer. [75]
Fibroblast Growth Factor Receptor
Fibroblast growth factor receptor (FGFR) is a membrane-bound tyrosine kinase which binds to fibroblast growth factor. [76] There are many isoforms which belong to a complex family of signaling molecules implicated in the growth and survival signals in normal and tumor cells, [77] angiogenesis, and inflammation [78] Signaling of FGF through FGFR is believed to be through paracrine and autocrine loops resulting in tumor blood vessel proliferation and survival as well as potential resistance mechanisms with Vascular endothelial growth factor (VEGF) and EGFR. [76],[79],[80],[81] Gly388ARG polymorphism is associated with a poor prognosis. [82],[83],[84] Mutations of FGFR are rare. [85],[86] FGFR is amplified in approximately 20% and appears to be particularly important in squamous histology NSCLC. [81] It is implicated in epithelial to mesenchymal transition responsible for invasion, metastasis and resistance to EGFR inhibition. [87] FGFR signaling appears to be important in squamous and large cell histology NSCLC where EGFR resistance is common. [76],[81],[88],[89] Currently, Small molecule inhibitors brivanib, dovitinib, Astra-Zeneca compound (AZD4547), and Taiho compound (TSU-68) are in clinical trials. A Soluble fusion protein FGF ligand trap, FP-1039 is in clinical trial as well. Monoclonal antibodies are currently in early development including AV369, AV269b, and AV370.
Vascular Endothelial Growth Factor
Angiogenesis is important in the development and maintenance of human tissues including malignancies. Angiogenesis has been studied and found to be promising in cancer since Dr. Folkman’s initial studies. [90] Vascular endothelial growth factor (VEGF) is believed to play a specific and crucial role in the regulation of angiogenesis and has been under investigation. [91],[92] Angiogenesis is an early event in tumor development and is important in tumor growth and metastasis. [91],[93],[94] The ability to feed tumor growth depends on the balance of many molecules released by tumor cells and the surrounding host tissue. [95],[96] There are many different processes involved in angiogenesis and involve many other mediators including multiple VEGFRs, plasminogen activators, matrix metallo-proteinases, transforming growth factor – Betas, and platelet-derived growth factor, inhibitors of matrix metalloproteinase, and many others. [97] As our knowledge has grown so has the number of agents which target angiogenesis. The ECOG 4599 trial was the first study in non-squamous cell lung cancer which showed some promising results for inhibition of angiogenesis with bevacizumab when added to carboplatin and paclitaxel. [98] There are many new small TKIs currently in development.
Ephrins and Their Receptors
Erythropoietin producing human (Eph hepatocellular carcinoma) is the largest group of RTKs in the genome. There are two classes of receptors A and B based on sequence conservation and mutual interactions or binding affinity. [99] In humans, there are a total of 14 Eph receptors known, in Class A, there are nine and class in B, there are five and eight Ephrin ligands for class A and B respectively. [100] Evidence suggests that Eph promotes tumor growth, invasion, metastasis, and neovascularization. Signaling between the ligands and/or receptors has emerged as likely key mechanism in tumor-suppressor function [101],[102],[103] Eph A2 and Eph B4 function as oncogenes however, there is conflicting evidence as they also appear to have tumor-suppressor function. [104],[105] Eph – RTKs, particularly within the A class appear to play a role in tumor progression as well as suppression. [101] EphA2 expression may be prognostic in NSCLC-adenocarcinoma for the development of metastatic disease, particularly CNS metastasis and is elevated in patients with a history of tobacco use. [101],[102] Conversely, low levels of EphA2 appear to be associated with a good prognosis. [101] Mutations in EphA2 appear to increase activation and promote invasion of the malignancy. [106] Multiple somatic mutations have been identified in Eph A3, frequently, mutations are found in adenocarcinoma of the lung and the role this plays is unclear. [101],[107],[108],[109],[110] In-vitro studies suggest a possible tumor suppressor role for Eph A3 in NSCLC. [101] Eph B3 correlates with tumor growth and promotion. [111] Cross-talk between Class A and B Eph may play a critical role in tumor regulation and tumor progression. [101] As we go forward, EPH targeting (especially EPHA2 and EPHB4) will likely become very important.
Braf
BRAF mutations have been reported in numerous solid tumors including melanoma, thyroid cancers, colorectal cancer, and some ovarian cancers. [112],[113],[114],[115] More recently, BRAF mutations have been described in NSCLC. [116],[117] There have been somatic mutations described predominately in females with lung adenocarcinoma which arise independent of smoking history. [118],[119] Additionally, BRAF mutations may also be found rarely in squamous cell carcinoma of the lung and may not be mutually exclusive with EGFR mutations. [118] BRAF mutations appear to be associated with a poor prognosis and frequently histologically showed micropapillary features. [118],[119] BRAF is believed to be involved in early events of lung cancer tumorigenesis. [120] Preclinical data suggest BRAF mutations might predict sensitivity of NSCLC cells to MEK inhibitors. [65],[121] BRAF inhibitors currently under development in NSCLC include Vemurafenib, GSK2118436, and CEP32496. MEK inhibitors under development in BRAF mutated NSCLC include Selumetinib.
Vaccines
Vaccines and immunotherapy have fallen out of favor until recently when re-exploration of this technique has revealed some limited responsiveness, although the lung cancer community remains cautiously optimistic. Past exploration with immune therapy has been unsuccessful due to the heterogeneity of lung cancer. Additionally, tumor response rates have been low and efficacy needs enhancement with combination therapy. The primary objective of vaccination is to provoke an adaptive antitumor immune response. [122],[123],[124] Numerous vaccines and immunotherapies are currently in clinical studies for NSCLC. These include MAGE-A3 which is a tumor-specific antigen present in 30-50% NSCLC patients. The MAGRIT phase III study for vaccination in NSCLC evaluates patients post-operatively with or without chemotherapy with disease-free survival as the primary endpoint. [125] MUC1 vaccination randomized MUC1-postive patients with advanced NSCLC to chemotherapy with or without vaccination. Initial studies demonstrated an increased OS hence a larger study is ongoing. [125]
PD-1/PDL-1
Treatment of cancer by immune response has been tried in many tumor types and has become the standard treatment in some malignancies such as melanoma. The immune system in the past has been pursued in lung cancer but, with only anecdotal success. Lung cancer is considered not to be responsive to immunotherapy. [126] Recently, there has been renewed interest in harnessing the immune response for treatment of lung cancer. Most interestingly, there has been much work with PD-1. Programmed death 1 (PD-1) protein is a T-cell coinhibitory receptor which is similar in structure to cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). [127] There are two known ligands for PD-1, PD-L1 (B7-H1), and PD-L2 (B7-DC). [128],[129],[130],[131] The interaction between PD-1 and PD-L1 has been shown to down-modulate T-cell responses in-vitro and in-vivo. [132],[133],[134],[135],[136]
In a recent trial, an objective response was noted in 5 of 49 patients (10%) with advanced NSCLC who received anti-PD-L1. [127] Additionally, in a companion trial evaluating anti-PD-1 antibody, an 18% response rate was seen in patients with NSCLC (14 of 76 patients. [137] Both studies did show durable responses with these therapies across all tumor types. [127],[137] Additional work is ongoing.
Conclusion
This is an exciting time in NSCLC research and treatment. There are numerous molecules which have been identified as potential treatment targets. There is a frenzy of research being carried out which, has begun to demonstrate on a molecular level the amount of histological and molecular heterogeneity which exists in NSCLC cells. Additionally, we now see that patients with some of these molecular targets may have new treatment options that may result in prolonged survival and improved quality of life. While we have made great advances, we have much more work ahead of us. All of these efforts and knowledge however, bring us closer to a more personalized approach to our patients’ care.
References
| 1. | Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012;62:10-29.  |
| 2. | Owonikoko T, Ramalingam SS, Behera M, et al. Survival Impact of Newly Approved Therapeutic Agents in Patients with Advanced Non-Small Cell Lung Cancer (NSCLC): A SEER-Medicare Database Analysis. J Clin Oncol 28:7633, 2010. |
| 3. | Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-8. [PUBMED] |
| 4. | Scagliotti G, Brodowicz T, Shepherd FA, Zielinski C, Vansteenkiste J, Manegold C, et al. Treatment-by-histology interaction analyses in three phase III trials show superiority of pemetrexed in nonsquamous non-small cell lung cancer. J Thorac Oncol 2011;6:64-70. |
| 5. | Ranson M, Hammond LA, Ferry D, Kris M, Tullo A, Murray PI, et al. ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: Results of a phase I trial. J Clin Oncol 2002;20:2240-50. [PUBMED] |
| 6. | Jänne PA, Meyerson M. ROS1 rearrangements in lung cancer: A new genomic subset of lung adenocarcinoma. J Clin Oncol 2012;30:878-9. |
| 7. | Kwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703. |
| 8. | Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 2010;362:2380-8. |
| 9. | Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009;361:947-57. |
| 10. | Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C, et al. Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med 2009;361:958-67. |
| 11. | Zhou C, Wu YL, Chen G, Feng J, Liu XQ, Wang C, et al. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): A multicentre, open-label, randomised, phase 3 study. Lancet Oncol 2011;12:735-42. |
| 12. | Fukuoka M, Yano S, Giaccone G, Tamura T, Nakagawa K, Douillard JY, et al. Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer (The IDEAL 1 Trial) corrected. J Clin Oncol 2003;21:2237-46. |
| 13. | Jänne PA, Gurubhagavatula S, Yeap BY, Lucca J, Ostler P, Skarin AT, et al. Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, “Iressa”) on an expanded access study. Lung Cancer 2004;44:221-30. |
| 14. | Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350:2129-39. |
| 15. | Paez JG, Jänne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 2004;304:1497-500. |
| 16. | Mitsudomi T, Morita S, Yatabe Y, Negoro S, Okamoto I, Tsurutani J, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): An open label, randomised phase 3 trial. Lancet Oncol 2010;11:121-8. |
| 17. | Rosell R, Carcereny E, Gervais R, Vergnenegre A, Massuti B, Felip E, et al. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): A multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012;13:239-46. |
| 18. | Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: A phase III trial – INTACT 1. J Clin Oncol 2004;22:777-84. |
| 19. | Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: A phase III trial – INTACT 2. J Clin Oncol 2004;22:785-94. |
| 20. | Heigener DF, Reck M. Mutations in the epidermal growth factor receptor gene in non-small cell lung cancer: Impact on treatment beyond gefitinib and erlotinib. Adv Ther 2011;28:126-33. |
| 21. | Ahrendt SA, Decker PA, Alawi EA, Zhu Yr YR, Sanchez-Cespedes M, Yang SC, et al. Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung. Cancer 2001;92:1525-30. |
| 22. | Slebos RJ, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJ, et al. K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 1990;323:561-5. |
| 23. | Graziano SL, Gamble GP, Newman NB, Abbott LZ, Rooney M, Mookherjee S, et al. Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 1999;17:668-75. |
| 24. | Roberts PJ, Stinchcombe TE, Der CJ, Socinski MA. Personalized medicine in non-small-cell lung cancer: Is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol 2010;28:4769-77. |
| 25. | Aviel-Ronen S, Blackhall FH, Shepherd FA, Tsao MS. K-ras mutations in non-small-cell lung carcinoma: A review. Clin Lung Cancer 2006;8:30-8. |
| 26. | Mascaux C, Iannino N, Martin B, Paesmans M, Berghmans T, Dusart M, et al. The role of RAS oncogene in survival of patients with lung cancer: A systematic review of the literature with meta-analysis. Br J Cancer 2005;92:131-9. |
| 27. | Cappuzzo F, Ciuleanu TE, Stelmakh S, Cicenas A, Szczesna E, Junasz E et al. Saturn: A double blind, randomized, phase III study of maintenance erlotinib versus placebo following nonprogression with first-line platinum-based chemotherapy in patients with advanced NSCLC. J Clin Oncol 2009;27:15s,2009 (abstr 8001) |
| 28. | Eberhard DA, Johnson BE, Amler LC, Goddard AD, Heldens SL, Herbst RS, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol 2005;23:5900-9. |
| 29. | Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): A randomised phase III trial. Lancet 2008;372:1809-18. |
| 30. | Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, et al. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label randomised phase III trial. Lancet 2009;373:1525-31. |
| 31. | Al-Mulla F, MacKenzie EM. Differences in in vitro invasive capacity induced by differences in Ki-Ras protein mutations. J Pathol 2001;195:549-56. |
| 32. | Al-Mulla F, Milner-White EJ, Going JJ, Birnie GD. Structural differences between valine-12 and aspartate-12 Ras proteins may modify carcinoma aggression. J Pathol 1999;187:433-8. |
| 33. | Span M, Moerkerk PT, De Goeij AF, Arends JW. A detailed analysis of K-ras point mutations in relation to tumor progression and survival in colorectal cancer patients. Int J Cancer 1996;69:241-5. |
| 34. | Winder T, Mündlein A, Rhomberg S, Dirschmid K, Hartmann BL, Knauer M, et al. Different types of K-Ras mutations are conversely associated with overall survival in patients with colorectal cancer. Oncol Rep 2009;21:1283-7. |
| 35. | Repasky GA, Chenette EJ, Der CJ. Renewing the conspiracy theory debate: Does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol 2004;14:639-47. |
| 36. | Douillard J, Hirsh V, Mok TS, Socinski MA, Watkins C, Lowe E, et al. Molecular and clinical subgroup analyses from a phase III trial comparing gefitinib with docetaxel in previously treated non-small cell lung cancer (INTEREST). J Clin Oncol 2008;26:8001, (May 20 suppl; abstr 8001^) |
| 37. | Khambata-Ford S, Harbison CT, Hart LL, Awad M, Xu LA, Horak CE, et al. Analysis of potential predictive markers of cetuximab benefit in BMS099, a phase III study of cetuximab and first-line taxane/carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 2010;28:918-27. |
| 38. | O’Byrne KJ, Bondarenko I, Barrios C, Eschbach C, Martens U, Hotko Y et al. Molecular and Clinical predictors of outcome for cetuximab in non-small cell lung cancer (NSCLC): Data from the FLEX study. J Clin Oncol 2009;27:15s, 2009 (abstr 8007) |
| 39. | Balko JM, Jones BR, Coakley VL, Black EP. MEK and EGFR inhibition demonstrate synergistic activity in EGFR-dependent NSCLC. Cancer Biol Ther 2009;8:522-30. |
| 40. | Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, et al. Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 2008;14:1351-6. |
| 41. | Mahoney CL, Choudhury B, Davies H, Edkins S, Greenman C, Haaften Gv, et al. LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition. Br J Cancer 2009;100:370-5. |
| 42. | Kim ES, Herbst RS, Wistuba II, Lee JJ, Blumenschein GR Jr, Tsao A, et al. The BATTLE trial: Personalizing therapy for lung cancer. Cancer Discov 2011;1:44-53. |
| 43. | Sadiq AA, Geynisman DM, Salgia R. Inhibition of MET receptor tyrosine kinase and its ligand hepatocyte growth factor. J Thorac Oncol 2011;6:S1810-1. |
| 44. | Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol 2003;4:915-25. |
| 45. | Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007;316:1039-43. |
| 46. | Xu L, Kikuchi E, Xu C, Ebi H, Ercan D, Cheng KA, et al. Combined EGFR/MET or EGFR/HSP90 inhibition is effective in the treatment of lung cancers codriven by mutant EGFR containing T790M and MET. Cancer Res 2012;72:3302-11 |
| 47. | Danilkovitch-Miagkova A, Angeloni D, Skeel A, Donley S, Lerman M, Leonard EJ. Integrin-mediated RON growth factor receptor phosphorylation requires tyrosine kinase activity of both the receptor and c-Src. J Biol Chem 2000;275:14783-6. |
| 48. | Oh JJ, West AR, Fishbein MC, Slamon DJ. A candidate tumor suppressor gene, H37, from the human lung cancer tumor suppressor locus 3p21.3. Cancer Res 2002;62:3207-13. |
| 49. | Sutherland LC, Wang K, Robinson AG. RBM5 as a putative tumor suppressor gene for lung cancer. J Thorac Oncol 2010;5:294-8. |
| 50. | Choong NW, Salgia R, Vokes EE. Key signaling pathways and targets in lung cancer therapy. Clin Lung Cancer 2007;8:S52-60. |
| 51. | Choong NW, Ma PC, Salgia R. Therapeutic targeting of receptor tyrosine kinases in lung cancer. Expert Opin Ther Targets 2005;9:533-59. |
| 52. | Ghigna C, De Toledo M, Bonomi S, Valacca C, Gallo S, Apicella M, et al. Pro-metastatic splicing of Ron proto-oncogene mRNA can be reversed: Therapeutic potential of bifunctional oligonucleotides and indole derivatives. RNA Biol 2010;7:495-503. |
| 53. | Kanteti R, Krishnaswamy S, Catenacci D, Tan YH, EL-Hashani E, Cervantes G, et al. Differential expression of RON in small and non-small cell lung cancers. Genes Chromosomes Cancer 2012;51:841-51 |
| 54. | Zinser GM, Leonis MA, Toney K, Pathrose P, Thobe M, Kader SA, et al. Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation. Cancer Res 2006;66:11967-74. |
| 55. | Kawano O, Sasaki H, Endo K, Suzuki E, Haneda H, Yukiue H, et al. PIK3CA mutation status in Japanese lung cancer patients. Lung Cancer 2006;54:209-15. |
| 56. | Kawano O, Sasaki H, Okuda K, Yukiue H, Yokoyama T, Yano M, et al. PIK3CA gene amplification in Japanese non-small cell lung cancer. Lung Cancer 2007;58:159-60. |
| 57. | Yamamoto H, Shigematsu H, Nomura M, Lockwood WW, Sato M, Okumura N, et al. PIK3CA mutations and copy number gains in human lung cancers. Cancer Res 2008;68:6913-21. |
| 58. | Janku F, Stewart DJ, Kurzrock R. Targeted therapy in non-small-cell lung cancer – Is it becoming a reality? Nat Rev Clin Oncol 2010;7:401-14. |
| 59. | West KA, Linnoila IR, Belinsky SA, Harris CC, Dennis PA. Tobacco carcinogen-induced cellular transformation increases activation of the phosphatidylinositol 3′- kinase/Akt pathway in vitro and in vivo. Cancer Res 2004;64:446-51. |
| 60. | Ludovini V, Bianconi F, Pistola L, Pistola V, Chiari R, Colella R, et al. Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations. Cancer Chemother Pharmacol 2012;69:1289-99. |
| 61. | Kang S, Bader AG, Vogt PK. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci U S A 2005;102:802-7. |
| 62. | Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011;3:75ra26. |
| 63. | Ludovini V, Bianconi F, Pistola L, Chiari R, Minotti V, Colella R, et al. Phosphoinositide-3-kinase catalytic alpha and KRAS mutations are important predictors of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer. J Thorac Oncol 2011;6:707-15. |
| 64. | Cuffe S, Leighl NB. Targeting the phosphatidylinosital 3-kinase, Akt, and mammalian target of rapamycin pathway in non-small cell lung cancer. J Thorac Oncol 2011;6:S1805-7. |
| 65. | Janku F, Garrido-Laguna I, Petruzelka LB, Stewart DJ, Kurzrock R. Novel therapeutic targets in non-small cell lung cancer. J Thorac Oncol 2011;6:1601-12. |
| 66. | Bergethon K, Shaw AT, Ou SH, Katayama R, Lovly CM, McDonald NT, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol 2012;30:863-70. |
| 67. | Hofstra RM, Landsvater RM, Ceccherini I, Stulp RP, Stelwagen T, Luo Y, Pasini B et al. A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma. Nature 1994;367:375-6. |
| 68. | Eng C. RET proto-oncogene in the development of human cancer. J Clin Oncol 1999;17:380-93. |
| 69. | Ju YS, Lee WC, Shin JY, Lee S, Bleazard T, Won JK, et al. A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing. Genome Res 2012;22:436-45. |
| 70. | Li F, Feng Y, Fang R, Fang Z, Xia J, Han X, et al. Identification of RET gene fusion by exon array analyses in “pan-negative” lung cancer from never smokers. Cell Res 2012;22:928-31. |
| 71. | Lipson D, Capelletti M, Yelensky R, Otto G, Parker A, Jarosz M, et al. Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies. Nat Med 2012;18:382-4. |
| 72. | Takeuchi K, Soda M, Togashi Y, Suzuki R, Sakata S, Hatano S, et al. RET, ROS1 and ALK fusions in lung cancer. Nat Med 2012;18:378-81. |
| 73. | Wang R, Hu H, Pan Y, Li Y, Ye T, Li C, et al. RET Fusions Define a Unique Molecular and Clinicopathologic Subtype of Non-Small-Cell Lung Cancer. J Clin Oncol 2012;30:4352-9. |
| 74. | Kohno T, Ichikawa H, Totoki Y, Yasuda K, Hiramoto M, Nammo T, et al. KIF5B-RET fusions in lung adenocarcinoma. Nat Med 2012;18:375-7. |
| 75. | Liebner DA, Shah MH. Thyroid cancer: Pathogenesis and targeted therapy. Ther Adv Endocrinol Metab 2011;2:173-95. |
| 76. | Marek L, Ware KE, Fritzsche A, Hercule P, Helton WR, Smith JE, et al. Fibroblast growth factor (FGF) and FGF receptor-mediated autocrine signaling in non-small-cell lung cancer cells. Mol Pharmacol 2009;75:196-207. |
| 77. | Riess JW, Neal JW. Targeting FGFR, ephrins, Mer, MET, and PDGFR-α in non-small cell lung cancer. J Thorac Oncol 2011;6:S1797-8. |
| 78. | Beenken A, Mohammadi M. The FGF family: Biology, pathophysiology and therapy. Nat Rev Drug Discov 2009;8:235-53. |
| 79. | Ellis LM, Hicklin DJ. Pathways mediating resistance to vascular endothelial growth factor-targeted therapy. Clin Cancer Res 2008;14:6371-5. |
| 80. | Kono SA, Marshall ME, Ware KE, Heasley LE. The fibroblast growth factor receptor signaling pathway as a mediator of intrinsic resistance to EGFR-specific tyrosine kinase inhibitors in non-small cell lung cancer. Drug Resist Updat 2009;12:95-102. |
| 81. | Weiss J, Sos ML, Seidel D, Peifer M, Zander T, Heuckmann JM, et al. Frequent and focal FGFR1 amplification associates with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 2010;2:62ra93. |
| 82. | Falvella FS, Frullanti E, Galvan A, Spinola M, Noci S, De Cecco L, et al. FGFR4 Gly388Arg polymorphism may affect the clinical stage of patients with lung cancer by modulating the transcriptional profile of normal lung. Int J Cancer 2009;124:2880-5. |
| 83. | Matakidou A, El Galta R, Rudd MF, Webb EL, Bridle H, Eisen T, et al. Further observations on the relationship between the FGFR4 Gly388Arg polymorphism and lung cancer prognosis. Br J Cancer 2007;96:1904-7. |
| 84. | Spinola M, Leoni V, Pignatiello C, Conti B, Ravagnani F, Pastorino U, et al. Functional FGFR4 Gly388Arg polymorphism predicts prognosis in lung adenocarcinoma patients. J Clin Oncol 2005;23:7307-11. |
| 85. | Grose R, Dickson C. Fibroblast growth factor signaling in tumorigenesis. Cytokine Growth Factor Rev 2005;16:179-86. |
| 86. | Korc M, Friesel RE. The role of fibroblast growth factors in tumor growth. Curr Cancer Drug Targets 2009;9:639-51. |
| 87. | Yauch RL, Januario T, Eberhard DA, Cavet G, Zhu W, Fu L, et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res 2005;11:8686-98. |
| 88. | Semrad TJ, Mack PC. Fibroblast growth factor signaling in non-small-cell lung cancer. Clin Lung Cancer 2012;13:90-5. |
| 89. | Ware KE, Marshall ME, Heasley LR, Marek L, Hinz TK, Hercule P, et al. Rapidly acquired resistance to EGFR tyrosine kinase inhibitors in NSCLC cell lines through de-repression of FGFR2 and FGFR3 expression. PLoS One 2010;5:e14117. |
| 90. | Folkman J. What is the evidence that tumors are angiogenesis dependent? J Natl Cancer Inst 1990;82:4-6. |
| 91. | Politi A, Mameli S, Acquati F, Galli M, Zerboni S, Michi R, et al. Acute myocardial infarction during labor: Report of a case and review of the literature. Ital Heart J Suppl 2001;2:795-8. |
| 92. | Poon RT, Fan ST, Wong J. Clinical implications of circulating angiogenic factors in cancer patients. J Clin Oncol 2001;19:1207-25. |
| 93. | Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992;267:10931-4. |
| 94. | Keith RL, Miller YE, Gemmill RM, Drabkin HA, Dempsey EC, Kennedy TC, et al. Angiogenic squamous dysplasia in bronchi of individuals at high risk for lung cancer. Clin Cancer Res 2000;6:1616-25. |
| 95. | Carmeliet P. Mechanisms of angiogenesis and arteriogenesis. Nat Med 2000;6:389-95. |
| 96. | Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996;86:353-64. |
| 97. | Otrock ZK, Mahfouz RA, Makarem JA, Shamseddine AI. Understanding the biology of angiogenesis: Review of the most important molecular mechanisms. Blood Cells Mol Dis 2007;39:212-20. |
| 98. | Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. |
| 99. | Surawska H, Ma PC, Salgia R. The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev 2004;15:419-33. |
| 100. | Nasarre P, Potiron V, Drabkin H, Roche J. Guidance molecules in lung cancer. Cell Adh Migr 2010;4:130-45. |
| 101. | Brantley-Sieders DM. Clinical relevance of Ephs and ephrins in cancer: Lessons from breast, colorectal, and lung cancer profiling. Semin Cell Dev Biol 2012;23:102-8. |
| 102. | Brantley-Sieders DM, Chen J. Eph receptor tyrosine kinases in angiogenesis: From development to disease. Angiogenesis 2004;7:17-28. |
| 103. | Pasquale EB. Eph receptors and ephrins in cancer: Bidirectional signalling and beyond. Nat Rev Cancer 2010;10:165-80. |
| 104. | Norden-Zfoni A, Desai J, Manola J, Beaudry P, Force J, Maki R, et al. Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res 2007;13:2643-50. |
| 105. | Wykosky J, Debinski W. The EphA2 receptor and ephrinA1 ligand in solid tumors: Function and therapeutic targeting. Mol Cancer Res 2008;6:1795-806. |
| 106. | Faoro L, Singleton PA, Cervantes GM, Lennon FE, Choong NW, Kanteti R, et al. EphA2 mutation in lung squamous cell carcinoma promotes increased cell survival, cell invasion, focal adhesions, and mammalian target of rapamycin activation. J Biol Chem 2010;285:18575-85. |
| 107. | Alam SM, Fujimoto J, Jahan I, Sato E, Tamaya T. Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers. Br J Cancer 2008;98:845-51. |
| 108. | Davies H, Hunter C, Smith R, Stephens P, Greenman C, Bignell G, et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res 2005;65:7591-5. |
| 109. | Greenman C, Stephens P, Smith R, Dalgliesh GL, Hunter C, Bignell G, et al. Patterns of somatic mutation in human cancer genomes. Nature 2007;446:153-8. |
| 110. | Lloyd JM, McIver CM, Stephenson SA, Hewett PJ, Rieger N, Hardingham JE. Identification of early-stage colorectal cancer patients at risk of relapse post-resection by immunobead reverse transcription-PCR analysis of peritoneal lavage fluid for malignant cells. Clin Cancer Res 2006;12:417-23. |
| 111. | Ji XD, Li G, Feng YX, Zhao JS, Li JJ, Sun ZJ, et al. EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration. Cancer Res 2011;71:1156-66. |
| 112. | Curtin JA, Fridlyand J, Kageshita T, Patel HN, Busam KJ, Kutzner H, et al. Distinct sets of genetic alterations in melanoma. N Engl J Med 2005;353:2135-47. |
| 113. | Kimura ET, Nikiforova MN, Zhu Z, Knauf JA, Nikiforov YE, Fagin JA. High prevalence of BRAF mutations in thyroid cancer: Genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma. Cancer Res 2003;63:1454-7. |
| 114. | Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA, et al. Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 2005;65:6063-9. |
| 115. | Singer G, Oldt R 3 rd , Cohen Y, Wang BG, Sidransky D, Kurman RJ, et al. Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma. J Natl Cancer Inst 2003;95:484-6. |
| 116. | Brose MS, Volpe P, Feldman M, Kumar M, Rishi I, Gerrero R, et al. BRAF and RAS mutations in human lung cancer and melanoma. Cancer Res 2002;62:6997-7000. |
| 117. | Naoki K, Chen TH, Richards WG, Sugarbaker DJ, Meyerson M. Missense mutations of the BRAF gene in human lung adenocarcinoma. Cancer Res 2002;62:7001-3. |
| 118. | Marchetti A, Felicioni L, Malatesta S, Grazia Sciarrotta M, Guetti L, Chella A, et al. Clinical features and outcome of patients with non-small-cell lung cancer harboring BRAF mutations. J Clin Oncol 2011;29:3574-9. |
| 119. | Yousem SA, Nikiforova M, Nikiforov Y. The histopathology of BRAF-V600E-mutated lung adenocarcinoma. Am J Surg Pathol 2008;32:1317-21. |
| 120. | Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010;363:809-19. |
| 121. | Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res 2008;68:9375-83. |
| 122. | Dermime S, Armstrong A, Hawkins RE, Stern PL. Cancer vaccines and immunotherapy. Br Med Bull 2002;62:149-62. |
| 123. | Kelly RJ, Giaccone G. Lung cancer vaccines. Cancer J 2011;17:302-8. |
| 124. | Nencioni A, Grüenbach F, Patrone F, Brossart P. Anticancer vaccination strategies. Ann Oncol 2004;15:iv153-60. |
| 125. | Ujhazy P, Carbone D. Summary of presentations from the 11 th targeted therapies for lung cancer meeting: Immunotherapy and vaccines for treatment of lung cancer. J Thorac Oncol 2011;6:S1815-7. |
| 126. | Holt GE, Podack ER, Raez LE. Immunotherapy as a strategy for the treatment of non-small-cell lung cancer. Therapy 2011;8:43-54. |
| 127. | Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65. |
| 128. | Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 1999;5:1365-9. |
| 129. | Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-34. |
| 130. | Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2001;2:261-8. |
| 131. | Tseng SY, Otsuji M, Gorski K, Huang X, Slansky JE, Pai SI, et al. B7-DC, a new dendritic cell molecule with potent costimulatory properties for T cells. J Exp Med 2001;193:839-46. |
| 132. | Butte MJ, Keir ME, Phamduy TB, Sharpe AH, Freeman GJ. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses. Immunity 2007;27:111-22. |
| 133. | Butte MJ, Peña-Cruz V, Kim MJ, Freeman GJ, Sharpe AH. Interaction of human PD-L1 and B7-1. Mol Immunol 2008;45:3567-72. |
| 134. | Park JJ, Omiya R, Matsumura Y, Sakoda Y, Kuramasu A, Augustine MM, et al. B7-H1/CD80 interaction is required for the induction and maintenance of peripheral T-cell tolerance. Blood 2010;116:1291-8. |
| 135. | Paterson AM, Brown KE, Keir ME, Vanguri VK, Riella LV, Chandraker A, et al. The programmed death-1 ligand 1:B7-1 pathway restrains diabetogenic effector T cells in vivo. J Immunol 2011;187:1097-105. |
| 136. | Yang J, Riella LV, Chock S, Liu T, Zhao X, Yuan X, et al. The novel costimulatory programmed death ligand 1/B7.1 pathway is functional in inhibiting alloimmune responses in vivo. J Immunol 2011;187:1113-9. |
| 137. | Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012;366:2443-54. |
Authors
Dr.Victoria Meucci Villaflor, University of Chicago Medicine 5841 South Maryland Avenue, MC 2115 Chicago.
Dr.Ravi Salgia, University of Chicago Medicine 5841 South Maryland Avenue, MC 2115 Chicago.