Abstract
Expression of factors including EGFR, HER2, and P2Y receptors confers ALK inhibitor resistance in NSCLC.
Major finding: Expression of factors including EGFR, HER2, and P2Y receptors confers ALK inhibitor resistance in NSCLC.
Approach: Candidate resistance drivers were identified using a large-scale functional genetic screen.
Impact: Signatures associated with resistance drivers were enriched in crizotinib-resistant patient tumors.
Although anaplastic lymphoma kinase (ALK) inhibitors, such as crizotinib and the second-generation inhibitor ceritinib, are clinically effective for treating patients with non–small cell lung cancer (NSCLC) with ALK rearrangements, resistance commonly develops within a year. To identify genes that are sufficient to confer ALK inhibitor resistance in ALK-rearranged NSCLC cells, Wilson and colleagues conducted a large-scale functional screen of 12,800 human genes using a publicly available open-reading frame (ORF) library. Validation analysis identified 61 ORFs representing 54 genes that promoted resistance to crizotinib and the second-generation inhibitor TAE684 in ALK-dependent NSCLC cells, including known resistance drivers such as AXL and HGF, as well as previously unidentified candidate genes. Approximately half of the resistance ORFs reactivated the AKT and/or ERK pathways in the presence of ALK inhibition, and 38 ALK resistance drivers also conferred resistance to EGFR inhibition in EGFR-mutant NSCLC cell lines, suggesting the existence of shared resistance mechanisms. Expression of the top candidate resistance driver, neureglin-1, induced resistance in ALK-dependent NSCLC cells via activation of HER2/HER3 signaling. In addition, expression of P2Y purinergic receptors resulted in decreased ALK inhibitor sensitivity and increased NSCLC cell survival. P2Y receptor–driven resistance was mediated, in part, by downstream activation of protein kinase C, which was sufficient to confer resistance to ALK inhibitors and was reversed by dual treatment with a pan-PKC inhibitor. Importantly, analysis of gene signatures enriched in ALK-rearranged lung tumors from patients who had developed crizotinib resistance as compared with treatment-naïve tumors revealed five signatures that were associated with resistance pathways identified by the functional screen, including HER2, RAF1, P2Y, and two independent EGFR signatures. These results highlight multiple pathways that drive clinical resistance to ALK inhibition in lung cancer and suggest potential combinatorial therapeutic strategies that may overcome or delay resistance.
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