The Resistance to EGFR-TKIs in Non-Small Cell Lung Cancer: From Molecular Mechanisms to Clinical Application of New Therapeutic Strategies

Abstract

Almost 17% of Western patients affected by non-small cell lung cancer (NSCLC) have an activating epidermal growth factor receptor (EGFR) gene mutation. Del19 and L858R are the most-common ones; they are positive predictive factors for EGFR tyrosine kinase inhibitors (TKIs). Currently, osimertinib, a third-generation TKI, is the standard first-line therapy for advanced NSCLC patients with common EGFR mutations. This drug is also administered as a second-line treatment for those patients with the T790M EGFR mutation and previously treated with first- (erlotinib, gefitinib) or second- (afatinib) generation TKIs. However, despite the high clinical efficacy, the prognosis remains severe due to intrinsic or acquired resistance to EGRF-TKIs. Various mechanisms of resistance have been reported including the activation of other signalling pathways, the development of secondary mutations, the alteration of the downstream pathways, and phenotypic transformation. However, further data are needed to achieve the goal of overcoming resistance to EGFR-TKIs, hence the necessity of discovering novel genetic targets and developing new-generation drugs. This review aimed to deepen the knowledge of intrinsic and acquired molecular mechanisms of resistance to EGFR-TKIs and the development of new therapeutic strategies to overcome TKIs’ resistance.

What the future holds: BBT-176, beyond third-generation EGFR tyrosine kinase inhibitors

“…Lung cancer holds the record in terms of cancer-related mortality in the world; non-small cell lung cancer (NSCLC) is the most frequent subtype ( 1 ). For many years, platinum-based chemotherapy has represented the only therapeutic strategy for advanced NSCLC patients although with a poor survival benefit ( 2 ).…”

“…In the last decade, some NSCLC oncogenic drivers were discovered, and consequently, new targeted drugs were developed providing an impressive amelioration of overall survival (OS) for selected patients. The epidermal growth factor receptor (EGFR) gene mutations are the most important oncogenic drivers ( 1 ). In fact, several EGFR-tyrosine kinase inhibitors (EGFR-TKIs) became standard therapies for NSCLC patients with activating EGFR gene mutations.…”

“…The remaining mutations are called uncommon and include rare EGFR mutations and complex EGFR mutations, accounting for 10–15%; they have variable predictive values ( 6 ). In addition, it is not rare to find a combination of EGFR mutations ( 1 ).…”

“…However, the clinical efficacy of osimertinib is limited due to the occurrence of acquired resistance, usually related to the development of EGFR C797S mutation [10–25% in second-line, 7% in first-line settings ( 1 , 9 )]. It corresponds to a tertiary point mutation, consisting of substitution of the cysteine with serine within the adenosine triphosphate (ATP)-binding site.…”

“…It corresponds to a tertiary point mutation, consisting of substitution of the cysteine with serine within the adenosine triphosphate (ATP)-binding site. This change prevents the constitution of the covalent bond of osimertininb to mutant EGFR ( 1 ). Moreover, this mutation is responsible for cross-resistance to all other third-generation EGFR TKIs, such as narzartinib and rociletinib because of their similar binding models ( 10 ).…”