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

SIMPLE SUMMARY: Lung cancer is a devastating disease, with non-small cell lung cancer (NSCLC) being the most common subtype. With the development of novel targeted therapeutics, survival times have continuously improved over the past two decades. In a subset of NSCLC, gene rearrangements of the anaplastic lymphoma kinase (ALK), or gene fusions involving ALK, can be determined. ALK-inhibitors are increasingly used as a standard of care in patients with ALK gene abnormalities, and can also be administered as first-line treatment in advanced-stage NSCLC. However, over the disease course, cancers tend to develop resistance mechanisms, warranting the switch from first- to second- or third-generation ALK inhibitors. With this literature review, we aim to give a concise overview about these resistance mechanisms, and what kind of sequential treatment may be feasible if therapy failure upon an ALK inhibitor occurs. 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.