Current Knowledge about Mechanisms of Drug Resistance against ALK Inhibitors in Non-Small Cell Lung Cancer

Abstract

Non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer subtypes. Two to seven percent of NSCLC patients harbor gene rearrangements of the anaplastic lymphoma kinase (ALK) gene or, alternatively, harbor chromosomal fusions of ALK with echinoderm microtubule-associated protein-like 4 (EML4). The availability of tyrosine kinase inhibitors targeting ALK (ALK-TKIs) has significantly improved the progression-free and overall survival of NSCLC patients carrying the respective genetic aberrations. Yet, increasing evidence shows that primary or secondary resistance to ALK-inhibitors during the course of treatment represents a relevant clinical problem. This necessitates a switch to second- or third-generation ALK-TKIs and a close observation of NSCLC patients on ALK-TKIs during the course of treatment by repetitive molecular testing. With this review of the literature, we aim at providing an overview of current knowledge about resistance mechanisms to ALK-TKIs in NSCLC.

First-Line Anaplastic Lymphoma Kinase (ALK) Inhibitors for ALK-Positive Lung Cancer in Asian Populations: Systematic Review and Network Meta-Analysis

“…Despite its tremendous therapeutic efficacy, drug resistance to crizotinib develops eventually in almost all cases. Most often, secondary ALK gene mutations in the kinase domain, such as L1196M, G1269A, and G1202R, account for the mechanism of drug resistance [ 25 ]. Furthermore, the occurrence of secondary mutations seems to differ by ethnicity.…”

Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells

“…9 Princess Maxima Center for Pediatric Oncology, Utrecht, The Netherlands. 10 Molecular Diagnostics Department, The Institute of Cancer Research and Clinical Genomics, The Royal Marsden NHS Foundation, London, UK. 11 Cancer Section, UCL Great Ormond Street Institute of Child Health, London, UK.…”

“…As observed with other targeted therapies, resistance to ALK inhibitors frequently occurs in ALK-driven cancer. While mechanisms leading to ALK inhibitor resistance in cancers with ALK fusion genes have been extensively studied [10], the mechanisms in tumors containing activating ALK mutations or ALK amplifications are largely unknown.…”

Anaplastic lymphoma kinase-special immunity and immunotherapy

“…The development and application of ALK inhibitors have made outstanding contributions to the treatment of ALK+ tumor patients, and it is still the main choice for first-line treatment ( 112 ). However, to date, resistance to ALK inhibitors has proven unavoidable in all cases ( 113 ). For TKIs resistant patients, the exploration of immunotherapy is currently a promising treatment direction.…”