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

Introduction to EGFR sensitising and resistance mutations

Data based on an analysis of tumour specimens from 155 patients with EGFR-mutant lung cancers at the time of acquired resistance to gefitinib or erlotinib therapy.

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