Updated Evidence on the Mechanisms of Resistance to ALK Inhibitors and Strategies to Overcome Such Resistance: Clinical and Preclinical Data

Abstract

Anaplastic lymphoma kinase(ALK) rearrangement is one of the oncogenes in non-small cell lung cancer (NSCLC) identified in 2007. The PROFILE trials demonstrated that patients with ALK-rearranged NSCLC can be successfully treated with crizotinib, and that crizotinib is superior to chemotherapy in both first- and second-line settings. Furthermore, next-generation ALK inhibitors, such as alectinib and ceritinib, have been shown to harbor excellent efficacy for NSCLC patients with ALK rearrangement. However, it is known that many cases ultimately acquire resistance to ALK inhibitors. Some potential mechanisms of resistance to ALK inhibitors are as follows: ALK dominant resistance, such as secondary mutations and copy number gain in the ALK gene; activation of the bypass tracks, including EGFR, KRAS, KIT, MET, and IGF-1R. Furthermore, treatment strategies to overcome these resistance mechanisms have been proposed, and next-generation ALK inhibitors, agents which inhibit the bypass tracks, and heat shock protein 90 inhibitors are thought to be promising. Thus, clinical and pre-clinical evidence on the resistance mechanisms to ALK inhibitors and treatment strategies to overcome the resistance have been gradually obtained. Herein, we concisely review the current clinical and pre-clinical data regarding the mechanisms of resistance to ALK inhibitors and treatments to overcome such resistance.

Metastatic Anaplastic Lymphoma Kinase-1 (ALK-1)-Rearranged Inflammatory Myofibroblastic Sarcoma to the Brain with Leptomeningeal Involvement: Favorable Response to Serial ALK Inhibitors: A Case Report

“…Mechanisms responsible for resistance to crizotinib may be due to acquired ALK gene mutations, and activation of other signaling bypass pathway [24,25]. It also has been shown that multiple mechanisms of resistances may occur in the same ALK resistant tumor [26,27]. …”

ALK‐rearrangement in non‐small‐cell lung cancer (NSCLC)

“…The last type of ALK gene mutation is point mutation. Secondary resistance is an acquired mechanism after the tumor has been exposed to an ALK inhibitor and most types of resistance are caused by mutations in the target ALK gene, resulting in an inability to inhibit the encoded tyrosine kinase . The first drug resistance point mutations identified were C1156Y and L1196M .…”

The Potent ALK Inhibitor Brigatinib (AP26113) Overcomes Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in Preclinical Models

“…ALK-dependent mechanisms of resistance, observed in approximately 30% of patients, include the acquisition of secondary mutations in ALK that interfere with crizotinib binding and/or amplification of the ALK fusion gene. More than 10 secondary mutations in ALK have been associated with crizotinib resistance in patients, with the most common being L1196M and G1269A (4,5). The central nervous system (CNS) is the first site of progression in approximately 50% of patients (6,7), suggesting inadequate penetration into the CNS by crizotinib (i.e., pharmacologic failure) as the primary cause of resistance in these patients.…”