Molecular resistance mechanisms of ALK inhibitors and implications for therapeutic management of ALK-rearranged lung cancer patients

Dysregulated anaplastic lymphoma kinase (ALK) protein expression has been previously reported in non-Hodgkin’s lymphoma (NHL) (1). However, it was not until 2007 when Soda et al. and others revealed that ALK is constitutively activated in some patients with non-small cell lung cancer (NSCLC), due to ALK gene rearrangement (2,3). In NSCLC, ALK rearrangement results in expression of ALK fusion proteins with aberrant ALK signalling and oncogenic transformation (2) and occurs in about 3–5% of the total NSCLCs (4). Currently, the treatment strategy of so-called ALK rearranged NSCLC relies on selection of an ALK tyrosine kinase inhibitor (TKI). The first in class ALK inhibitor crizotinib was developed and approved through accelerated drug approval by the US Food and Drug Administration (FDA) in 2011 on the basis of high response rates in early phase evaluation (5,6) and was granted regular approval by US FDA in 2013 based on demonstration of superior progression-free survival (PFS) and overall response rate (RR) for crizotinib-treated patients compared to chemotherapy (7).