Abstract 3148: Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer

Anaplastic lymphoma kinase (ALK) fusion oncogenes occur in around 3%-5% non-small cell lung cancer (NSCLC) cases. Various ALK inhibitors are in clinical use for the treatment of ALK-NSCLC, including the first generation ALK inhibitor, Crizotinib, and recently the more highly potent Alectinib and Ceritinib. However, most tumors eventually become resistant to ALK specific inhibitors. To address the mechanisms underlying the development of ALK inhibitor resistance, we used iTRAQ quantitative mass spectrometry and phosphor-receptor tyrosine kinase arrays to investigate intracellular signaling alterations in ALK inhibitor resistant NSCLC cell lines. Src signaling was identified as an Alectinib resistance mechanism, and combination treatment with ALK and Src inhibitors was highly effective for inhibiting the growth of ALK inhibitor resistant cells in vitro and in mouse xenograft models. Furthermore, phospho-receptor tyrosine kinase activation and downstream PI3K/AKT signaling was effectively blocked by inhibiting Src in Alectinib resistant cells. Finally, we showed that the combined use of ALK and Src inhibitors inhibited the growth of other ALK-NSCLC cell lines, including those that were Ceritinib or Lorlatinib resistant. Our data suggest that targeting Src signaling may be an effective approach to the treatment of ALK–NSCLC with acquired resistance to ALK inhibitors. Citation Format: Ryohei Yoshida, Takaaki Sasaki, Shunsuke Okumura, Yoshinobu Ohsaki. Activation of Src signaling mediates acquired resistance to ALK inhibition in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3148. doi:10.1158/1538-7445.AM2017-3148