Induction of autophagy contributes to crizotinib resistance in ALK-positive lung cancer

Abstract

Use of the inhibitor of ALK fusion onco-protein, crizotinib (PF02341066), has achieved impressive clinical efficacy in patients with ALK-positive non-small cell lung cancer. Nevertheless, acquired resistance to this drug occurs inevitably in approximately a year, limiting the therapeutic benefits of this novel targeted therapy. In this study, we found that autophagy was induced in crizonitib-resistant lung cancer cells and contributed to drug resistance. We observed that ALK was downregulated in the crizotinib-resistant lung cancer cell line, H3122CR-1, and this was causally associated with autophagy induction. The degree of crizotinib resistance correlated with autophagic activity. Activation of autophagy in crizotinib-resistant H3122CR-1 cells involved alteration of the Akt/mTOR signaling pathway. Furthermore, we demonstrated that chloroquine, an inhibitor of autophagy, could restore sensitivity of H3122CR-1 to crizotinib and enhance its efficacy against drug-resistant lung cancer. Thus, modulating autophagy may be worth exploring as a new strategy to overcome acquired crizonitib resistance in ALK-positive lung cancer.

Anaplastic lymphoma kinase rearrangement in lung Cancer: Its biological and clinical significance

“…In vivo analyses showed that imatinib could overcome the resistance occurring via the KIT amplification [77]. In addition, a recent study indicated the involvement of autophagy in the crizotinib resistance in an ALK-rearranged lung cancer cell line, which could be overcome by an inhibitor of autophagy, chloroquine [79]. Various treatment strategies to overcome these mechanisms of resistance have been developed, including second-generation ALK inhibitors and the use of HSP90 inhibitors [80,81].…”

Anaplastic lymphoma tyrosine kinase oncogene in human cancer: gene aberrations, methods of detection and therapeutic potential

“…On the contrary, ALK-independent resistance involves other mechanisms not associated with ALK gene, for example mutations occurrence in EGFR and KRAS gene, c-kit amplification, or histological shift (Table 2). 68,69,[71][72][73][74] Furthermore, some ALK-rearranged patients with a disease progression after crizotinib treatment showed two different resistance mechanisms in the same tumor. 71 In this context, second-generation ALK inhibitors have been developed in order to overcome resistance to crizotinib, especially these new inhibitors have showed high efficacy against both the ALK secondary mutations and the ALK-independent resist- (Table 3).…”

Therapeutic management of ALK+nonsmall cell lung cancer patients

“…Another mechanism of resistance relates to the emergence of clones with activation of alternative proliferation pathways such as EGFR [72][73][74], HSP90 [75][76][77], PI3K AKT mTOR [78], cKIT amplifications [72] or insulin-like growth factor 1 receptor (IGF1R) [79]. This mechanism accounts for approximately 20% of reported cases of crizotinib escape [80].…”