Abstract 5262: Identifying the role of AXL in fusion kinase inhibitor resistant non-small cell lung cancer

Abstract

Abstract Chromosomal rearrangements involving ALK, ROS1, RET and others generate novel fusion kinases which comprise approximately 10% of the oncogenic drivers in lung adenocarcinoma. Several tyrosine kinase inhibitors (TKIs) are approved or in development for each of these oncogenes and have shown marked clinical improvement for patients, but resistance inevitably occurs, a significant proportion of which is not currently druggable. AXL is a receptor tyrosine kinase that is often upregulated in resistant cancers in response to both chemotherapy and targeted therapies such as EGFR inhibitors. AXL can promote resistance to targeted therapy by signaling through the MAPK and Akt pathways or heterodimerizing with other receptors to maintain growth and survival signaling. However, the role of AXL in mediating resistance to ALK, ROS1, and RET TKIs is not well understood. In screening our unique panel of patient-derived lung adenocarcinoma cell lines harboring ALK, ROS1 or RET gene fusions, we found elevated AXL expression was correlated with resistance to cognate TKIs, as well as mesenchymal features including spindle morphology and vimentin expression. Combining the AXL inhibitor R428 with TKI treatment, such as crizotinib for ALK and ROS1 driven cell lines, was effective at inhibiting colony formation and wound healing in fusion kinase inhibitor resistant cell lines. Combination treatment downregulates Akt phosphorylation in resistant cells, and we found the resistant cell lines were also more sensitive to PI3K inhibition than cell lines that are still sensitive to their specific TKI. Interestingly, we also identified AXL cross talk with other receptor tyrosine kinases. In a RET inhibitor resistant model expression of both AXL and EGFR are elevated and the receptors interact, which can be disrupted upon EGF stimulation, to drive resistance. Collectively, we show that AXL upregulation is a common marker of TKI resistance among ALK, ROS1, and RET fusion kinase driven lung adenocarcinoma models, and provide rationale for AXL as a clinical target for combination therapy to overcome drug resistance. Citation Format: Tara Peters, Anastasios Dimou, Anh Le, Robert Doebele. Identifying the role of AXL in fusion kinase inhibitor resistant non-small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5262.