Abstract 406: Mechanism of AXL regulation in chemotherapy resistance

Abstract Constitutive activation of receptor tyrosine kinase AXL is an important phenomenon in chemotherapy resistance and is highly expressed in several malignancies. Although studies over the past decade revealed that AXL is upregulated during treatment, the biological significance and the mechanism by which AXL is activated upon chemotherapy are yet to be determined. In this study, we aim to understand the biology of AXL mediated chemo-resistance, and the consequences of AXL activation. To investigate the biological significance of AXL, we generated iRFP-luciferase-expressing cell lines which facilitate live monitoring of cancer progression during treatment in an in vivo setting. In parallel, by knocking down AXL using shRNA, we observed inhibitory effect on cell migration and tumor forming efficiency in vitro. Moreover, using in vitro cell based models, we showed that while AXL expression was upregulated upon treatment with chemotherapeutic agents, pharmacological inhibition of AXL caused synergistic effect between selective AXL inhibitors and cisplatin. Additionally, our data suggest that upregulation of AXL and its tyrosine phosphorylation may mediate resistance to chemotherapy. Using phosphoproteomics, we identified a link between CDK9 activation and drug-induced AXL expression. We showed that while AXL expression was upregulated upon treatment with tyrosine kinase inhibitor, pharmacological inhibition of CDK9 completely blocked AXL expression. Collectively, our data suggest that activation of kinase signaling might be required for AXL repression, and thereby, for targeting AXL-axis in chemotherapy resistance. Citation Format: Mehreen Ahmed, Julhash Uddin Kazi. Mechanism of AXL regulation in chemotherapy resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 406.