期刊论文详细信息
Biomarker Research
EGFR inhibition in non-small cell lung cancer: current evidence and future directions
Alexander Chi2  Scot Remick3  William Tse1 
[1] Department of Hematology and Oncology, West Virginia University, Morgantown, WV, 26506, USA
[2] Department of Radiation Oncology, West Virginia University, Morgantown, WV, 26506, USA
[3] Mary-Babb Randolph Cancer Center, West Virginia University, Morgantown, WV, 26506, USA
关键词: Resistance;    Radiotherapy;    EGFR mutations;    NSCLC;    EGFR;   
Others  :  792161
DOI  :  10.1186/2050-7771-1-2
 received in 2012-10-09, accepted in 2012-10-12,  发布年份 2013
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【 摘 要 】

EGFR inhibition has emerged to be an important strategy in the treatment of non-small cell lung cancer (NSCLC). Small molecule tyrosine kinase inhibitors (TKIs) and mono-clonal antibodies (mAbs) to the EGFR have been tested in multiple large randomized phase III studies alone or combined with chemotherapy, as well as small phase I-II studies which investigated their efficacy as radiosensitizers when combined with radiotherapy. In this review, we described the current clinical outcome after treatment with EGFR TKIs and mAbs alone or combined with chemotherapy in advanced stage NSCLC, as well as the early findings in feasibility/phase I or II studies regarding to whether EGFR TKI or mAb can be safely and effectively combined with radiotherapy in the treatment of locally advanced NSCLC. Furthermore, we explore the potential predictive biomarkers for response to EGFR TKIs or mAbs in NSCLC patients based on the findings in the current clinical trials; the mechanisms of resistance to EGFR inhibition; and the strategies of augmenting the antitumor activity of the EGFR inhibitors alone or when combined with chemotherapy or radiotherapy.

【 授权许可】

   
2013 Chi et al.; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer. J Clin Oncol 2003, 21:2787-2799.
  • [2]Yoshida T, Zhang G, Haura EB: Targeting epidermal growth factor receptor: Central signaling kinase in lung cancer. Biochem Pharmacol 2010, 80:613-623.
  • [3]Ono M, Kuwano M: Molecular mechanisms of epidermal growth factor receptor (EGFR) activation and response to gefitinib and other EGFR-targeting drugs. Clin Cancer Res 2006, 12:7242-7251.
  • [4]Cohen S: Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem 1962, 237:1555-1562.
  • [5]Ausborn NL, Le QT, Bradley JD, et al.: Molecular profiling to optimize treatment in non-small cell lung cancer: a review of potential molecular targets for radiation therapy by the translational research program of the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 2012, 83:e453-e464.
  • [6]Mendelsohn J, Baselga J: The EGF receptor family as targets for cancer therapy. Oncogene 2000, 19:6550-6565.
  • [7]Harari PM, Huang SM: Combining EGFR inhibitors with radiation or chemotherapy: will preclinical studies predict clinical results? Int J Radiat Oncol Biol Phys 2004, 58:976-983.
  • [8]Milas L, Fan Z, Andratschke NH, Ang KK: Epidermal growth factor receptor and tumor response to radiation: in vivo preclinical studies. Int J Radiat Oncol Biol Phys 2004, 58:966-971.
  • [9]Raben D, Helfrich B, Bunn PA: Targeted therapies for non-small-cell lung cancer: Biology, rationale, and preclinical results from a radiation oncology perspective. Int J Radiat Oncol Biol Phys 2004, 59:S27-38.
  • [10]Cappuzzo F, Hirsch FR, Rossi E, et al.: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small cell lung cancer. J Natl Cancer Inst 2005, 97:643-655.
  • [11]Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al.: Epidermal growth factor receptor in non-small cell lung carcinomas: correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 2003, 21:3798-3807.
  • [12]Herbst RS, Bunn PA: Targeting the epidermal growth factor receptor in non-small cell lung cancer. Clin Cancer Res 2003, 9:5813-5824.
  • [13]Raben D, Helfrich B, Chan DC, et al.: The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin Cancer Res 2005, 11:795-805.
  • [14]Cascone T, Morelli MP, Ciardiello F: Small molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer. Ann Oncol 2006, Suppl 2:ii46-ii48.
  • [15]Giaccone G, Herbst RS, Manegold C, 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, 22:777-784.
  • [16]Herbst RS, Giaccone G, Schiller JH, 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, 22:785-794.
  • [17]Herbst RS, Prager D, Hermann R, et al.: TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 2005, 23:5892-5899.
  • [18]Mok TS, Wu YL, Thongprasert S, et al.: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009, 361:947-957.
  • [19]Mitsudomi T, Morita S, Yatabe Y, et al.: Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG 3405): an open label, randomised phase 3 trial. Lancet Oncol 2010, 11:121-128.
  • [20]Zhou C, Wu Y, Chen G, 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, 12:735-742.
  • [21]Inoue A, Kobayash K, Maemondo M, et al.: Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002). Ann Oncol 2012. In press.
  • [22]Rosell R, Carcereny E, Gervais R, 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, 13:239-246.
  • [23]Gridelli C, Ciardiello F, Gallo C, et al.: First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: the TORCH randomized trial. J Clin Oncol 2012, 30:3002-3011.
  • [24]Lynch TJ, Bell DW, Sordella R, et al.: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Eng J Med 2004, 350:2129-2139.
  • [25]Yun CH, Boggon TJ, Li Y, et al.: Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell 2007, 11:217-227.
  • [26]Kobayashi S, Boggon TJ, Dayaram T, et al.: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 2005, 352:786-792.
  • [27]Pao W, Miller VA, Politi KA, et al.: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2005, 2:e73.
  • [28]Kim ES, Hirsh V, Mok T, et al.: Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet Oncol 2008, 372:1809-1818.
  • [29]Ciuleanu T, Stelmakh L, Cicenas S, et al.: Efficacy and safety of erlotinib versus chemotherapy in second-line treatment of patients with advanced, non-small-cell lung cancer with poor prognosis (TITAN): a randomized multicentre, open-label, phase 3 study. Lancet Oncol 2012, 13:300-308.
  • [30]Cappuzzo F, Ciuleanu T, Stelmakh L, et al.: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 2010, 11:521-529.
  • [31]Mendelsohn J, Baselga J: Epidermal growth factor receptor targeting in cancer. Semin Oncol 2006, 33:369-385.
  • [32]Rosell R, Robinet G, Szczesna A, et al.: Randomized phase II study of cetuximab plus cisplatin/ vinorelbine compared with cisplatin/ vinorelbine alone as first-line therapy in EGFR-expressing advanced non-small-cell lung cancer. Ann Oncol 2008, 19:362-369.
  • [33]Pirker R, Pereira J, Szczesna A, et al.: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet Oncol 2009, 373:1525-1531.
  • [34]Lynch TJ, Patel T, Dreisbach L, et al.: Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: results of the randomized multicenter phase III trial BMS099. J Clin Oncol 2010, 28:911-917.
  • [35]Douillard JY, Shepherd FA, Hirsh V, et al.: Molecular predictors of outcome with gefitinib and docetaxel in previously treated non-small-cell lung cancer: data from the randomized phase III INTEREST trial. J Clin Oncol 2010, 28:744-752.
  • [36]Brugger W, Triller N, Blasinska-Morawiec M, et al.: Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer. J Clin Oncol 2011, 29:4113-4120.
  • [37]Milella M, Nuzzo C, Bria E, et al.: EGFR molecular profiling in advanced NSCLC a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy. J Thorac Oncol 2012, 7:672-680.
  • [38]Cadranel J, Mauguen A, Faller M, et al.: Impact of systematic EGFR and KRAS mutation evaluation on progression-free survival and overall survival in patients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC Project-Part 2). J Thorac Oncol 2012, 7:1490-1502.
  • [39]Bai H, Mao L, Wang HS, et al.: Epidermal growth factor receptor mutations in plasma DNA samples predict tumor response in Chinese patients with stages IIIB to IV non-small-cell lung cancer. J Clin Oncol 2009, 27:2653-2659.
  • [40]Bell DW, Lynch TJ, Haserlat SM, et al.: Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 2005, 23:8081-8092.
  • [41]Eberhard DA, Johnson BE, Amler LC, 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, 23:5900-5909.
  • [42]Fukuoka M, Wu YL, Thongprasert S, et al.: Biomarker analysis and final overall survival results from a phase III, randomized, open-label, first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS). J Clin Oncol 2011, 29:2866-2874.
  • [43]Hirsch FR, Herbst RS, Olsen C, et al.: Increased EGFR gene copy number detected by fluorescent in situ hybridization predicts outcome in non-small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 2008, 26:3351-3357.
  • [44]Khambata-Ford S, Harbison CT, Hart LL, 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, 28:918-927.
  • [45]O’Byrne KJ, Gatzemeier U, Bondarenko I, et al.: Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 2011, 12:795-805.
  • [46]Begg AC, Stewart FA, Vens C: Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 2011, 11:239-253.
  • [47]Riesterer O, Milas L, Ang KK: Use of molecular biomarkers for predicting the response to radiotherapy with or without chemotherapy. J Clin Oncol 2007, 25:4075-4083.
  • [48]Bonner JA, Harari PM, Giralt J, et al.: Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol 2010, 11:21-28.
  • [49]Aupérin A, Le Péchoux C, Rolland E, et al.: Meta-analysis of concomitant versus sequential radiochemotherapy in locally advanced non-small-cell lung cancer. J Clin Oncol 2010, 28:2181-2190.
  • [50]Bianco C, Tortora G, Bianco R, et al.: Enhancement of antitumor activity of ionizing radiation by combined treatment with the selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 (Iressa). Clin Cancer Res 2002, 8:3250-3258.
  • [51]Park SY, Kim YM, Pyo H: Gefitinib radiosensitizes non-small cell lung cancer cells through inhibition of ataxia telangiectasia mutated. Mol Cancer 2010, 9:222. BioMed Central Full Text
  • [52]Tanaka T, Munshi A, Brooks C, et al.: Gefitinib radiosensitizes non-small cell lung cancer cells by suppressing cellular DNA repair capacity. Clin Cancer Res 2008, 14:1266-1273.
  • [53]Wang M, Morsbach F, Sander D, et al.: EGF receptor inhibition radiosensitizes NSCLC cells by inducing senescence in cells sustaining DNA double-strand breaks. Cancer Res 2011, 71:6261-6269.
  • [54]Akashi Y, Okamoto I, Iwasa T, et al.: Enhancement of the antitumor activity of ionizing radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 2008, 98:749-755.
  • [55]Okamoto I, Takahashi T, Okamoto H, et al.: Single-agent gefitinib with concurrent radiotherapy for locally advanced non-small cell lung cancer harboring mutations of the epidermal growth factor receptor. Lung Cancer 2011, 72:199-204.
  • [56]Choong NW, Mauer AM, Haraf DJ, et al.: Phase I trial of erlotinib-based multimodality therapy for inoperable stage III non-small cell lung cancer. J Thorac Oncol 2008, 3:1003-1011.
  • [57]Rothschild S, Bucher SE, Bernier J, et al.: Gefitinib in combination with irradiation with or without cisplatin in patients with inoperable stage III non-small cell lung cancer: a phase I trial. Int J Radiat Oncol Biol Phys 2011, 80:126-132.
  • [58]Wang J, Xia TY, Wang YJ, et al.: Prospective study of epidermal growth factor receptor tyrosine kinase inhibitors concurrent with individualized radiotherapy for patients with locally advanced or metastatic non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011, 81:e59-e65.
  • [59]Center B, Petty WJ, Ayala D, et al.: A phase I study of gefitinib with concurrent dose-escalated weekly docetaxel and conformal three-dimensional thoracic radiation followed by consolidative docetaxel and maintenance gefitinib for patients with stage III non-small cell lung cancer. J Thorac Oncol 2010, 5:69-74.
  • [60]Stinchcombe TE, Morris DE, Lee CB, et al.: Induction chemotherapy with carboplatin, irinotecan, and paclitaxel followed by high dose three-dimension conformal thoracic radiotherapy (74 Gy) with concurrent carboplatin, paclitaxel, and gefitinib in unresectable stage IIIA and stage IIIB non-small cell lung cancer. J Thorac Oncol 2008, 3:250-257.
  • [61]Ready N, Jänne PA, Bogart J, et al.: Chemoradiotherapy and gefitinib in stage III non-small cell lung cancer with epidermal growth factor receptor and KRAS mutation analysis Cancer and Leukemia Group B (CALEB) 30106, a CALGB-stratified phase II trial. J Thorac Oncol 2010, 5:1382-1390.
  • [62]Chang CC, Chi KH, Kao SJ, et al.: Upfront gefitinib/erlotinib treatment followed by concomitant radiotherapy for advanced lung cancer: a mon-institutional experience. Lung Cancer 2011, 73:189-194.
  • [63]Komaki RU, Kim YB, Wistuba II, et al.: Vimentin (EMT marker protein) score predicts resistance to erlotinib and radiotherapy for patients with stage III non-small cell lung cancer on a prospective phase II trial. J Thorac Oncol 2012, 7:S220.
  • [64]Curran WJ Jr, Paulus R, Langer C: Sequential vs concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG9410. JNCI 2011, 22:2499.
  • [65]Hanna N, Neubauer M, Yiannoutsos C, et al.: Phase III study of cisplatin, etoposide, and concurrent chest radiation with or without consolidation docetaxel in patients with inoperable stage III non-small-cell lung cancer: the Hoosier Oncology Group and U.S. Oncology. J Clin Oncol 2008, 26:5755-5760.
  • [66]Hughes S, Liong J, Miah A, et al.: A brief report on the safety study of induction chemotherapy followed by synchronous radiotherapy and cetuximab in stage III non-small cell lung cancer (NSCLC): SCRTACH study. J Thorac Oncol 2008, 3:648-651.
  • [67]Choi HJ, Sohn JH, Lee CG, et al.: A phase I study of nimotuzumab in combination with radiotherapy in stages IIB-IV non-small cell lung cancer unsuitable for radical therapy: Korean results. Lung Cancer 2011, 71:55-59.
  • [68]Bebb G, Smith C, Rorke S, et al.: Phase I clinical trial of the anti-EGFR monoclonal antibody nimotuzumab with concurrent external thoracic radiotherapy in Canadian patients diagnosed with stage IIB, III or IV non-small cell lung cancer unsuitable for radical therapy. Cancer Chemother Pharmacol 2011, 67:837-845.
  • [69]Govindan R, Bogart J, Stinchcombe T, et al.: Randomized phase II study of pemetrexed, carboplatin, and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small-cell lung cancer: Cancer and Leukemia Group B Trial 30407. J Clin Oncol 2011, 29:3120-3125.
  • [70]Jensen AD, Münter MW, Bischoff HG, et al.: Combined treatment of nonsmall cell lung cancer NSCLC stage III with intensity-modulated RT radiotherapy and cetuximab: the NEAR trial. Cancer 2011, 117:2988-2994.
  • [71]Hallqvist A, Wagenius G, Rylander H, et al.: Concurrent cetuximab and radiotherapy after docetaxel-cisplatin induction chemotherapy in stage III NSCLC: Satellite-A phase II study from the Swedish Lung Cancer Study Group. Lung Cancer 2011, 71:166-172.
  • [72]Blumenschein GR Jr, Paulus R, Curran WJ, et al.: Phase II study of cetuximab in combination with chemoradiation in patients with stage IIIA/B non-small-cell lung cancer: RTOG 0324. J Clin Oncol 2011, 29:2312-2318.
  • [73]Hammerman PS, Pänne PA, Johnson BE: Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2009, 15:7502-7509.
  • [74]Engelman JA, Zejnullahu K, Mitsudomi T, et al.: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007, 316:1039-1042.
  • [75]Yun CH, Mengwasser KE, Toms AV, et al.: The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci USA 2008, 105:2070-2075.
  • [76]Su KY, Chen HY, Li KC, et al.: Pretreatment epidermal growth factor receptor (EGFR) T790M mutation predicts shorter EGFR tyrosine kinase inhibitor response duration in patients with non-small-cell lung cancer. J Clin Oncol 2012, 30:433-440.
  • [77]Miller VA, Hirsh V, Cadranel J, et al.: Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial. Lancet Oncol 2012, 13:528-538.
  • [78]Yang J CH, Schuler MH, Yamamoto N, et al.: LUX-Lung 3: a randomized, open-label, phase III study of afatinib versus pemetrexed and cisplatin as first-line treatment for patients with advanced adenocarcinoma of the lung harboring EGFR-activating mutations. Abstract, ASCO 2012.
  • [79]Nakagawa T, Takeuchi S, Yamada T, et al.: Combined therapy with mutant-selective EGFR inhibitor and Met kinase inhibitor for overcoming erlotinib resistance in EGFR-mutant lung cancer. Mol Cancer Ther 2012, 11:2149-2157.
  • [80]Ohashi K, Sequist LV, Arcila ME, et al.: Lung cancers with acquired resistance to EGFR inhibitors occasionally harbor BRAF gene mutations but lack mutations in KRAS, NRAS, or MEK1. Proc Natl Acad Sci USA 2012, 109:E2127-E2133.
  • [81]Yamamoto C, Basaki Y, Kawahara A, et al.: Loss of PTEN expression by blocking nuclear translocation of EGR1 in gefitinib-resistant lung cancer cells harboring epidermal growth factor receptor-activating mutations. Cancer Res 2010, 70:8715-8725.
  • [82]Roberts PJ, Stinchcombe TE, Der CJ, et al.: 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, 28:4769-4777.
  • [83]Linardou H, Dahabreh IJ, Kanaloupiti D, et al.: Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: a systematic review and meta-analysis of studies in advanced non-smll-cell lung cancer and metastatic colorectal cancer. Lancet Oncol 2008, 9:962-972.
  • [84]Huang S, Armstrong EA, Benavente S, et al.: Dual-agent molecular targeting of the epidermal growth factor receptor (EGFR): combining anti-EGFR antibody with tyrosine kinase inhibitor. Cancer Res 2004, 64:5355-5362.
  • [85]Choi EJ, Ryu YK, Kim SY, et al.: Targeting epidermal growth factor receptor-associated signaling pathways in non-small cell lung cancer cells: implications in radiation response. Mol Cancer Res 2010, 8:1027-1036.
  • [86]Nagata Y, Takahashi A, Ohnishi K, et al.: Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status. Int J Oncol 2010, 37:1001-1010.
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