Chromosomal rearrangements of ALK can result in a fusion protein that serves as an oncogenic driver in non-small cell lung cancer (NSCLC). Although patients with ALK-positive (ALK+) lung cancer have significant response rates when treated with tyrosine kinase inhibitors (TKIs), resistance against ALK targeted therapy consistently develops. Here, we modeled acquired resistance to ALK TKI therapy using 5 different FDA-approved ALK TKIs, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib, using two distinct ALK+ lung cancer cell lines, H3122 and STE-1 (10 resistant cell lines total). Both of these cell lines harbor an EML4-ALK E13;A20 fusion and were derived from patients prior to ALK directed therapy. An ALK kinase domain mutation (F1174L) was detected in the H3122 ceritinib resistant cells, but none of the other resistant cell lines harbored mutations in the ALK kinase domain known to confer TKI resistance. For each of the cell lines tested, we found that ALK TKI treatment in TKI-resistant cells failed to inhibit MAP kinase pathway activity. We hypothesized that inhibition of the MAP kinase pathway, via MEK inhibition, could restore drug sensitivity. The allosteric MEK inhibitors, trametinib and binimetinib, did not effectively reduce cell viability as single agents. However, ALK TKI co-treatment with a MEK inhibitor resensitized these cells by reducing cell viability in a synergistic manner across all ALK TKI-resistant cell lines tested. Whole transcriptomic analysis of ALK TKI-resistant cell lines also revealed an upregulation in EGFR and HER2 mRNA levels. These results provide rationale for combined ALK+MEK inhibitor therapy in patients who have relapsed on first line ALK TKI therapy.

Citation Format: Vincent Huang, Yingjun Yan, Huan Qiao, Yunkai Zhang, Christine M. Lovly. Parallel activation of MEK as a mechanism of resistance to ALK inhibitor therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 316.