Introduction to EGFR sensitising and resistance mutations
Introduction to EGFR sensitising and resistance mutations
A number of genetic drivers of tumour growth have been identified in patients with non-small cell lung cancer (NSCLC), including mutations in the epidermal growth factor receptor (EGFR) gene.1–3 EGFR activating mutations are found in exons 18 to 21 of the EGFR gene, which is part of the gene coding for the tyrosine kinase domain of the EGFR protein. In patients diagnosed with advanced NSCLC, the most common activating mutations observed are exon 19 deletions and an L858R point mutation in exon 21.4–8
Testing for ALK rearrangements and EGFR mutations at primary diagnosis of advanced NSCLC is recommended to guide treatment decisions.9,10 In patients diagnosed with advanced NSCLC and harbouring an ALK rearrangement or an activating or sensitising EGFR mutation, first-line treatment with an ALK-tyrosine kinase inhibitor (TKI) or EGFR-TKI is recommended.9,10
The majority of patients with an EGFR sensitising mutation will progress on treatment with an EGFR-TKI.11 At disease progression, mutation testing can be used to help identify the mechanism(s) of acquired resistance. Known resistance mechanisms include additional EGFR resistance mutations (e.g. T790M), alternative pathway activations (e.g. HER2 or MET amplification) or phenotypic transformations (to small-cell lung cancer [SCLC] or epithelial-mesenchymal transition).
The most common mechanism of acquired resistance to EGFR-TKIs is the EGFR T790M mutation, which occurs with an amino acid substitution at position 790 in EGFR, from a threonine (T) to a methionine (M).
The diagram below outlines the known resistance mechanisms to EGFR-TKIs.12
Mechanisms of acquired resistance to EGFR-TKIs
The development of resistance mutations leads to the nullification of the inhibitory activity of EGFR-TKIs. In the case of T790M, mutation at the so-called ‘gatekeeper’ amino acid 79013 renders EGFR refractory to EGFR-TKIs via steric hindrance and increased ATP affinity.14,15 Other secondary mutations in EGFR that have been linked to acquired resistance to EGFR-TKIs include D761Y and T854A (gefitinib and erlotinib only) and L747S (gefitinib only).16–18
Amplification of HER2 and MET have been implicated in the acquired resistance to EGFR-TKIs (gefitinib and erlotinib only) in patients with EGFRm NSCLC.19,20 It is understood that the amplification of these genes leads to the upregulation of parallel signalling pathways, thereby negating the inhibition by EGFR-TKIs.21
Mutations in downstream effector molecules of the EGFR signalling pathway (e.g. PIK3CA, BRAF) have been implicated in acquired resistance to EGFR-TKIs.22,23
Reduced expression of NF1 has been associated with EGFR-TKI resistance through activating RAS and the downstream RAS-ERK pathway.24
Acquired resistance to EGFR-TKIs may also be the result of histological transformation of NSCLC to SCLC, with persistence of the initial EGFR mutation in some cases.23
Further details on EGFR mutations and subsequent testing are available throughout EGFR-mutation.com.
- Kris MG et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI’s Lung Cancer Mutation Consortium (LCMC). J Clin Oncol 2011; 29(Suppl): Abstract CRA7506.
- Dearden S et al. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol 2013; 24: 2371–2376.
- Mendelsohn J, Baselga J. The EGF receptor family as targets for cancer therapy. Oncogene 2000; 19: 6550–6656.
- Yoshida K, Yatabe Y, Park J et al. Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer. J Thorac Oncol 2007; 2: 22–28.
- Mok TS, Wu YL, Thongprasert S et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–957.
- Sequist LV, Yang JC, Yamamoto N et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol 2013; 31: 3327–3334.
- Wu YL, Zhou C, Hu CP et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol 2014; 15: 213–222.
- Schuette W, Schirmacher P, Eberhardt WE et al. EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study. Epidemiol Biomarkers Prev 2015; 24: 1254–1261.
- NCCN. NCCN Clinical Practice Guidelines in Oncology NSCLC (version 4.2017), 2017. Available at: https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed 25 January 2017.
- Novello S et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2016; 27 (Suppl 5): v1-v27.
- Lee CK, Wu YL, Ding PN et al. Impact of specific epidermal growth factor receptor (EGFR) mutations and clinical characteristics on outcomes after treatment with EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR-mutant lung cancer: a meta-analysis. J Clin Oncol 2015; 33: 1958-1965.
- Yu HA, Arcila ME, Rekhtman N et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res 2013; 19: 2240–2247.
- Cross DA, Ashton SE, Ghiorghiu S et al. AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. Cancer Discov 2014; 4: 1046–1061.
- 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.
- 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 U S A 2008; 105: 2070–2075.
- Balak MN, Gong Y, Riely GJ et al. Novel D761Y and common secondary T790M mutations in epidermal growth factor receptor-mutant lung adenocarcinomas with acquired resistance to kinase inhibitors. Clin Cancer Res 2006; 12: 6494–6501.
- Bean J, Riely GJ, Balak M et al. Acquired resistance to epidermal growth factor receptor kinase inhibitors associated with a novel T854A mutation in a patient with EGFR-mutant lung adenocarcinoma. Clin Cancer Res 2008; 14: 7519–7525.
- Costa DB1, Halmos B, Kumar A et al. BIM mediates EGFR tyrosine kinase inhibitor-induced apoptosis in lung cancers with oncogenic EGFR mutations. PLoS Med 2007; 4: 1669–1679.
- Engelman JA, Zejnullahu K, Mitsudomi T et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science 2007; 316: 1039–1043.
- Takezawa K, Pirazzoli V, Arcila ME et al. HER2 amplification: a potential mechanism of acquired resistance to EGFR inhibition in EGFR-mutant lung cancers that lack the second-site EGFRT790M mutation. Cancer Discov 2012; 2: 922–933.
- Stewart EL, Tan SZ, Liu G et al. Known and putative mechanisms of resistance to EGFR targeted therapies in NSCLC patients with EGFR mutations – a review. Transl Lung Cancer Res 2015; 4: 67–81.
- 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 U S A 2012; 109: E2127–E2133.
- Sequist LV, Waltman BA, Dias-Santagata D et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med 2011; 3: 75ra26.
- de Bruin EC, Cowell C, Warne PH et al. Reduced NF1 expression confers resistance to EGFR inhibition in lung cancer. Cancer Discov 2014; 4: 606–619.