Review

Pharmacogenetics of EGFR in lung cancer: perspectives and clinical applications

Clara Mayo

Pangaea Biotech, Laboratory of Oncology, USP Dexeus University Institute, Sabino Arana, 5–19, 08028 Barcelona, Spain

Search for more papers by this author

Jordi Bertran-Alamillo

Pangaea Biotech, Laboratory of Oncology, USP Dexeus University Institute, Sabino Arana, 5–19, 08028 Barcelona, Spain

Search for more papers by this author

Miguel Ángel Molina-Vila

* Author for correspondence

Pangaea Biotech, Laboratory of Oncology, USP Dexeus University Institute, Sabino Arana, 5–19, 08028 Barcelona, Spain.

Search for more papers by this author

Email the corresponding author at mamolina@pangaeabiotech.com

Ana Giménez-Capitán

Pangaea Biotech, Laboratory of Oncology, USP Dexeus University Institute, Sabino Arana, 5–19, 08028 Barcelona, Spain

Search for more papers by this author

Carlota Costa

Pangaea Biotech, Laboratory of Oncology, USP Dexeus University Institute, Sabino Arana, 5–19, 08028 Barcelona, Spain

Search for more papers by this author

Rafael Rosell

Pangaea Biotech, Laboratory of Oncology, USP Dexeus University Institute, Sabino Arana, 5–19, 08028 Barcelona, Spain

Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916 Badalona, Spain

Search for more papers by this author

Published Online:17 May 2012https://doi.org/10.2217/pgs.12.54

View article

Abstract

Lung cancer is a lethal disease, and most cases have already disseminated at the time of diagnosis. Driver mutations in the EGFR tyrosine kinase domain (mainly deletions in exon 19 and L858R mutation in exon 21) have been identified in lung adenocarcinomas, mostly in never smokers, at frequencies of 20–60%. The EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib attain a response rate of 70% and progression-free survival of 9–13 months, although there are subgroups of patients with long-lasting remissions. No significant correlation between EGFR overexpression and response to treatment has been found, while controversial results have been reported regarding EGFR gene amplification. The pretreatment presence of the T790M mutation, initially identified as an acquired resistance mutation to treatment with EGFR TKIs, has also been reported and may indicate a genetically distinct disease. Finally, other genetic factors, such as mRNA expression of BRCA1 and components of the NF-κB pathway, can modulate response to EGFR TKIs in EGFR-mutated patients.

Keywords:

Papers of special note have been highlighted as: ▪ of interest ▪▪ of considerable interest

References

1 Jemal A, Siegel R, Ward E et al. Cancer statistics, 2008. CA Cancer J. Clin.58(2),71–96 (2008).Crossref, Medline, Google Scholar
2 Gazdar AF. Personalized medicine and inhibition of EGFR signaling in lung cancer. N. Engl. J. Med.361(10),1018–1020 (2009).▪ Describes the potential for individualized selection of treatment as determined by the characteristics of the patient and the tumor.Crossref, Medline, CAS, Google Scholar
3 Pao W, Girard N. New driver mutations in non-small-cell lung cancer. Lancet Oncol.12(2),175–180 (2011).Crossref, Medline, CAS, Google Scholar
4 Cataldo VD, Gibbons DL, Perez-Soler R, Quintas-Cardama A. Treatment of non-small-cell lung cancer with erlotinib or gefitinib. N. Engl. J. Med.364(10),947–955 (2011).Crossref, Medline, CAS, Google Scholar
5 Costa DB, Kobayashi S, Tenen DG, Huberman MS. Pooled analysis of the prospective trials of gefitinib monotherapy for EGFR-mutant non-small cell lung cancers. Lung Cancer58(1),95–103 (2007).Crossref, Medline, Google Scholar
6 Rosell R, Moran T, Queralt C et al. Screening for epidermal growth factor receptor mutations in lung cancer. N. Engl. J. Med.361(10),958–967 (2009).▪▪ First prospective study on screening for EGFR mutations in patients with advanced non-small-cell lung cancer (NSCLC) in a Caucasian population, conducted by the Spanish Lung Cancer Group.Crossref, Medline, CAS, Google Scholar
7 Hammerman PS, Janne PA, Johnson BE. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin. Cancer Res.15(24),7502–7509 (2009).Crossref, Medline, CAS, Google Scholar
8 Engelman JA, Settleman J. Acquired resistance to tyrosine kinase inhibitors during cancer therapy. Curr. Opin. Genet. Dev.18(1),73–79 (2008).Crossref, Medline, CAS, Google Scholar
9 Rosell R, Molina MA, Costa C et al. Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations. Clin. Cancer Res.17(5),1160–1168 (2011).▪▪ Describes the influence on progression-free survival of the baseline T790M mutation and the expression of components of homologous recombination repair and nonhomologous end joining, in patients with EGFR mutations treated with erlotinib.Crossref, Medline, CAS, Google Scholar
10 Bivona TG, Hieronymus H, Parker J et al. FAS and NF-kappaB signalling modulate dependence of lung cancers on mutant EGFR. Nature471(7339),523–526 (2011).▪▪ Using in vitro and in vivo models, describes the implication of components of the NF-κB pathway in the modulation of response to EGFR tyrosine kinase inhibitor (TKI) treatment in EGFR-mutant lung cancer patients.Crossref, Medline, CAS, Google Scholar
11 Reguart N, Cardona AF, Carrasco E et al.BRCA1: a new genomic marker for non-small-cell lung cancer. Clin. Lung Cancer9(6),331–339 (2008).Crossref, Medline, CAS, Google Scholar
12 Sethi G, Ahn KS, Chaturvedi MM, Aggarwal BB. Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha. Oncogene26(52),7324–7332 (2007).Crossref, Medline, CAS, Google Scholar
13 Gazdar AF. Activating and resistance mutations of EGFR in non-small-cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene28(Suppl. 1),S24–S31 (2009).Crossref, Medline, CAS, Google Scholar
14 Kumar A, Petri ET, Halmos B, Boggon TJ. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J. Clin. Oncol.26(10),1742–1751 (2008).Crossref, Medline, CAS, Google Scholar
15 Pao W, Iafrate AJ, Su Z. Genetically informed lung cancer medicine. J. Pathol.223(2),230–240 (2010).Medline, Google Scholar
16 Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N. Engl. J. Med.358(11),1160–1174 (2008).Crossref, Medline, CAS, Google Scholar
17 De Luca A, Normanno N. Predictive biomarkers to tyrosine kinase inhibitors for the epidermal growth factor receptor in non-small-cell lung cancer. Curr. Drug Targets11(7),851–864 (2010).Crossref, Medline, CAS, Google Scholar
18 Gazdar AF, Minna JD. Deregulated EGFR signaling during lung cancer progression: mutations, amplicons, and autocrine loops. Cancer Prev. Res. (Phila.)1(3),156–160 (2008).Crossref, Medline, CAS, Google Scholar
19 Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proc. Natl Acad. Sci. USA89(10),4309–4313 (1992).Crossref, Medline, CAS, Google Scholar
20 Paez JG, Janne PA, Lee JC et al.EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science304(5676),1497–1500 (2004).▪▪ Along with [21], this study describes, for the first time, the presence of EGFR mutations in a subgroup of patients with NSCLC and the correlation of these mutations with clinical response to the TKI gefitinib.Crossref, Medline, CAS, Google Scholar
21 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. Engl. J. Med.350(21),2129–2139 (2004).▪▪ Along with [20], this study describes, for the first time, the presence of EGFR mutations in a subgroup of patients with NSCLC and the correlation of these mutations with clinical response to the TKI gefitinib.Crossref, Medline, CAS, Google Scholar
22 Mitsudomi T, Kosaka T, Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J. Clin. Oncol.11(3),190–198 (2006).Crossref, Medline, CAS, Google Scholar
23 Ji H, Li D, Chen L et al. The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. Cancer Cell9(6),485–495 (2006).Crossref, Medline, CAS, Google Scholar
24 Xin H, Herrmann A, Reckamp K et al. Antiangiogenic and antimetastatic activity of JAK inhibitor AZD1480. Cancer Res.71(21),6601–6610 (2011).Crossref, Medline, CAS, Google Scholar
25 Rosell R, Viteri S, Molina MA, Benlloch S, Taron M. Epidermal growth factor receptor tyrosine kinase inhibitors as first-line treatment in advanced nonsmall-cell lung cancer. Curr. Opin. Oncol.22(2),112–120 (2010).Crossref, Medline, CAS, Google Scholar
26 Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin–paclitaxel in pulmonary adenocarcinoma. N. Engl. J. Med.361(10),947–957 (2009).▪ First prospective Phase III study comparing gefitinib with carboplatin–paclitaxel as first-line treatment. Enrolled Asian patients, never or light smokers with adenocarcinomas.Crossref, Medline, CAS, Google Scholar
27 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 (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol.11(2),121–128 (2010).Crossref, Medline, CAS, Google Scholar
28 Maemondo M, Inoue A, Kobayashi K et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N. Engl. J. Med.362(25),2380–2388 (2010).Crossref, Medline, CAS, Google Scholar
29 Zhou C, Wu Y-L, 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.12,735–742 (2011).Crossref, Medline, CAS, Google Scholar
30 Takano T, Fukui T, Ohe Y et al.EGFR mutations predict survival benefit from gefitinib in patients with advanced lung adenocarcinoma: a historical comparison of patients treated before and after gefitinib approval in Japan. J. Clin. Oncol.26(34),5589–5595 (2008).Crossref, Medline, CAS, Google Scholar
31 Sequist LV, Martins RG, Spigel D et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J. Clin. Oncol.26(15),2442–2449 (2008).Crossref, Medline, CAS, Google Scholar
32 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.13(3),239–246 (2012).▪ First prospective randomized Phase III study in European advanced NSCLC patients with EGFR mutations, comparing first-line erlotinib with platinum-based chemotherapy.Crossref, Medline, CAS, Google Scholar
33 Gao G, Ren S, Li A et al. Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: a meta-analysis from 6 phase III randomized controlled trials. Int. J. Cancer doi:10.1002/ijc.27396 (2011) (Epub ahead of print).Google Scholar
34 Normanno N, De Luca A, Bianco C et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene366(1),2–16 (2006).Crossref, Medline, CAS, Google Scholar
35 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.97(9),643–655 (2005).Crossref, Medline, CAS, Google Scholar
36 Hirsch FR, Varella-Garcia M, Bunn PA Jr et al. Molecular predictors of outcome with gefitinib in a Phase III placebo-controlled study in advanced non-small-cell lung cancer. J. Clin. Oncol.24(31),5034–5042 (2006).Crossref, Medline, CAS, Google Scholar
37 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.28(5),744–752 (2010).Crossref, Medline, CAS, Google Scholar
38 Crino L, Cappuzzo F, Zatloukal P et al. Gefitinib versus vinorelbine in chemotherapy-naive elderly patients with advanced non-small-cell lung cancer (INVITE): a randomized, Phase II study. J. Clin. Oncol.26(26),4253–4260 (2008).Crossref, Medline, CAS, Google Scholar
39 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.29(31),4113–4120 (2011).Crossref, Medline, CAS, Google Scholar
40 Yatabe Y, Takahashi T, Mitsudomi T. Epidermal growth factor receptor gene amplification is acquired in association with tumor progression of EGFR-mutated lung cancer. Cancer Res.68(7),2106–2111 (2008).Crossref, Medline, CAS, Google Scholar
41 Hirsch FR, Varella-Garcia M, Dziadziuszko R et al. Fluorescence in situ hybridization subgroup analysis of TRIBUTE, a Phase III trial of erlotinib plus carboplatin and paclitaxel in non-small cell lung cancer. Clin. Cancer Res.14(19),6317–6323 (2008).Crossref, Medline, CAS, Google Scholar
42 Fukuoka M, Wu YL, Thongprasert S et al. Biomarker analyses 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.29(21),2866–2874 (2011).Crossref, Medline, CAS, Google Scholar
43 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.2(3),e73 (2005).Crossref, Medline, Google Scholar
44 Kobayashi S, Boggon TJ, Dayaram T et al.EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med.352(8),786–792 (2005).Crossref, Medline, CAS, Google Scholar
45 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. USA105(6),2070–2075 (2008).Crossref, Medline, CAS, Google Scholar
46 Blencke S, Ullrich A, Daub H. Mutation of threonine 766 in the epidermal growth factor receptor reveals a hotspot for resistance formation against selective tyrosine kinase inhibitors. J. Biol. Chem.278(17),15435–15440 (2003).Crossref, Medline, CAS, Google Scholar
47 Engelman JA, Mukohara T, Zejnullahu K et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J. Clin. Invest.116(10),2695–2706 (2006).Crossref, Medline, CAS, Google Scholar
48 Kuang Y, Rogers A, Yeap BY et al. Noninvasive detection of EGFR T790M in gefitinib or erlotinib resistant non-small cell lung cancer. Clin. Cancer Res.15(8),2630–2636 (2009).Crossref, Medline, CAS, Google Scholar
49 Arcila ME, Oxnard GR, Nafa K et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin. Cancer Res.17(5),1169–1180 (2011).Crossref, Medline, CAS, Google Scholar
50 Garcia-Olive I, Monso E, Andreo F et al. Endobronchial ultrasound-guided transbronchial needle aspiration for identifying EGFR mutations. Eur. Respir. J.35(2),391–395 (2010).Crossref, Medline, CAS, Google Scholar
51 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.30(4),433–440 (2012).Crossref, Medline, CAS, Google Scholar
52 Engelman JA, Zejnullahu K, Mitsudomi T et al.MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science316(5827),1039–1043 (2007).Crossref, Medline, CAS, Google Scholar
53 Yano S, Wang W, Li Q et al. Hepatocyte growth factor induces gefitinib resistance of lung adenocarcinoma with epidermal growth factor receptor-activating mutations. Cancer Res.68(22),9479–9487 (2008).Crossref, Medline, CAS, Google Scholar
54 Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci. Transl. Med.3(75),75ra26 (2011).▪▪ Emphasizes the mechanism of resistance to EGFR inhibitors and underscores the importance of rebiopsies throughout the course of the disease.Crossref, Medline, Google Scholar
55 Yauch RL, Januario T, Eberhard DA et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin. Cancer Res.11(24 Pt 1),8686–8698 (2005).Crossref, Medline, CAS, Google Scholar
56 Suda K, Tomizawa K, Fujii M et al. Epithelial to mesenchymal transition in an epidermal growth factor receptor-mutant lung cancer cell line with acquired resistance to erlotinib. J. Thorac. Oncol.6(7),1152–1161 (2011).Crossref, Medline, Google Scholar
57 Yao Z, Fenoglio S, Gao DC et al. TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proc. Natl Acad. Sci. USA107(35),15535–15540 (2010).Crossref, Medline, CAS, Google Scholar
58 Yamasaki F, Johansen MJ, Zhang D et al. Acquired resistance to erlotinib in A-431 epidermoid cancer cells requires down-regulation of MMAC1/PTEN and up-regulation of phosphorylated Akt. Cancer Res.67(12),5779–5788 (2007).Crossref, Medline, CAS, Google Scholar
59 Guix M, Faber AC, Wang SE et al. Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J. Clin. Invest.118(7),2609–2619 (2008).Medline, CAS, Google Scholar
60 Chmielecki J, Foo J, Oxnard GR et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci. Transl. Med.3(90),90ra59 (2011).Crossref, Medline, CAS, Google Scholar
61 Chaft JE, Oxnard GR, Sima CS et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib. Clin. Cancer Res.17(19),6298–6303 (2011).Crossref, Medline, CAS, Google Scholar
62 Zhou W, Ercan D, Chen L et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature462(7276),1070–1074 (2009).Crossref, Medline, CAS, Google Scholar
63 Sharma SV, Bell DW, Settleman J, Haber DA. Epidermal growth factor receptor mutations in lung cancer. Nat. Rev. Cancer7(3),169–181 (2007).Crossref, Medline, CAS, Google Scholar
64 Yap TA, Vidal L, Adam J et al. Phase I trial of the irreversible EGFR and HER2 kinase inhibitor BIBW 2992 in patients with advanced solid tumors. J. Clin. Oncol.28(25),3965–3972 (2010).Crossref, Medline, CAS, Google Scholar
65 Sequist LV, Besse B, Lynch TJ et al. Neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor: results of a Phase II trial in patients with advanced non-small-cell lung cancer. J. Clin. Oncol.28(18),3076–3083 (2010).Crossref, Medline, CAS, Google Scholar
66 Rho JK, Choi YJ, Jeon BS et al. Combined treatment with silibinin and epidermal growth factor receptor tyrosine kinase inhibitors overcomes drug resistance caused by T790M mutation. Mol. Cancer Ther.9(12),3233–3243 (2010).Crossref, Medline, CAS, Google Scholar
67 Maheswaran S, Sequist LV, Nagrath S et al. Detection of mutations in EGFR in circulating lung-cancer cells. N. Engl. J. Med.359(4),366–377 (2008).Crossref, Medline, CAS, Google Scholar
68 Prudkin L, Tang X, Wistuba Ii. Germ-line and somatic presentations of the EGFR T790M mutation in lung cancer. J. Thorac. Oncol.4(1),139–141 (2009).Crossref, Medline, Google Scholar
69 Inukai M, Toyooka S, Ito S et al. Presence of epidermal growth factor receptor gene T790M mutation as a minor clone in non-small cell lung cancer. Cancer Res.66(16),7854–7858 (2006).Crossref, Medline, CAS, Google Scholar
70 Janku F, Garrido-Laguna I, Petruzelka LB et al. Novel therapeutic targets in non-small cell lung cancer. J. Thorac. Oncol.6(9),1601–1612 (2011).Crossref, Medline, Google Scholar
71 Engelman JA. Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat. Rev. Cancer9(8),550–562 (2009).Crossref, Medline, CAS, Google Scholar
72 Carcereny E, Molina MA, Sanchez JJ et al. Mutations of the catalytic subunit alpha of PI3K (PIK3CA) in erlotinib-treated non-small-cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor (EGFR) mutations J. Clin. Oncol. (Suppl. abstract 7588),29 (2011).Google Scholar
73 Chaft JE, Arcila ME, Paik PK et al. Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma – rationale for comprehensive mutation profiling. Mol. Cancer Ther.11(2),485–491 (2011).Crossref, Medline, Google Scholar
74 Pao W, Wang TY, Riely GJ et al.KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med.2(1),e17 (2005).▪ Along with [84] (in ovarian cancer), this Phase II trial assesses the efficacy of olaparib in women with advanced breast cancer harboring BRCA1 or BRCA2 mutations.Crossref, Medline, Google Scholar
75 Massarelli E, Varella-Garcia M, Tang X et al.KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin. Cancer Res.13(10),2890–2896 (2007).Crossref, Medline, CAS, Google Scholar
76 Schmid K, Oehl N, Wrba F et al.EGFR/KRAS/BRAF mutations in primary lung adenocarcinomas and corresponding locoregional lymph node metastases. Clin. Cancer Res.15(14),4554–4560 (2009).Crossref, Medline, CAS, Google Scholar
77 Shrivastav M, De Haro LP, Nickoloff JA. Regulation of DNA double-strand break repair pathway choice. Cell Res.18(1),134–147 (2008).Crossref, Medline, CAS, Google Scholar
78 Taron M, Rosell R, Felip E et al. BRCA1 mRNA expression levels as an indicator of chemoresistance in lung cancer. Hum. Mol. Genet.13(20),2443–2449 (2004).Crossref, Medline, CAS, Google Scholar
79 Rosell R, Perez-Roca L, Sanchez JJ et al. Customized treatment in non-small-cell lung cancer based on EGFR mutations and BRCA1 mRNA expression. PLoS ONE4(5),e5133 (2009).Crossref, Medline, Google Scholar
80 Hegan DC, Lu Y, Stachelek GC et al. Inhibition of poly(ADP-ribose) polymerase down-regulates BRCA1 and RAD51 in a pathway mediated by E2F4 and p130. Proc. Natl Acad. Sci. USA107(5),2201–2206 (2010).Crossref, Medline, CAS, Google Scholar
81 Lee SG, Su ZZ, Emdad L, Sarkar D, Franke TF, Fisher PB. Astrocyte elevated gene-1 activates cell survival pathways through PI3K–Akt signaling. Oncogene27(8),1114–1121 (2008).Crossref, Medline, CAS, Google Scholar
82 Santarpia M, Magri I, Sanchez-Ronco M et al. mRNA expression levels and genetic status of genes involved in the EGFR and NF-kappaB pathways in metastatic non-small-cell lung cancer patients. J. Transl. Med.9,163 (2011).Crossref, Medline, CAS, Google Scholar
83 Audeh MW, Carmichael J, Penson RT et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet376(9737),245–251 (2010).Crossref, Medline, CAS, Google Scholar
84 Tutt A, Robson M, Garber JE et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet376(9737),235–244.▪ Along with [74] (in ovarian cancer), this Phase II trial assesses the efficacy of olaparib in women with advanced breast cancer harboring BRCA1 or BRCA2 mutations.Crossref, Medline, Google Scholar
85 Naumov GN, Nilsson MB, Cascone T et al. Combined vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR) blockade inhibits tumor growth in xenograft models of EGFR inhibitor resistance. Clin. Cancer Res.15(10),3484–3494 (2009).▪ Explores the potential utility of combined VEGFR/EGFR pathway inhibition in xenograft models of EGFR TKI resistance.Crossref, Medline, CAS, Google Scholar

Vol. 13, No. 7

Metrics

Downloaded 644 times

History

Published online 17 May 2012

Published in print May 2012

Information

Keywords

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

PDF download