Abstract B25: An actionable AXL-ABL2-TAZ signaling axis promotes lung adenocarcinoma metastasis to the brain

Abstract

Abstract Despite recent work to uncover the biologic mechanisms governing tumor cell metastasis to the brain, new therapeutic approaches for treating patients with brain-metastatic disease have remained elusive. Through the use of in vivo models of brain metastasis and relevant in vitro molecular biology techniques, we identify a novel and targetable autocrine signaling axis required for lung adenocarcinoma metastasis to the brain centered upon the transcriptional coactivator TAZ. Nuclear localization of TAZ drives transcription of target genes AXL and ABL2, which in turn engage in bidirectional tyrosine kinase signaling at the protein level. Activation of ABL2 in turn increases TAZ stability and promotes its nuclear localization, establishing an autocrine feed-forward signaling loop and revealing a previously undescribed mechanism of TAZ nuclear localization dependent on tyrosine kinase activity of ABL2. We further reveal that the Neural Adhesion Molecule L1 (L1CAM), previously identified as a critical mediator of brain metastasis, is a direct target gene of TAZ whose expression is regulated by activation of AXL-ABL2-TAZ signaling. Our findings provide evidence for AXL and ABL2 kinase inhibitors as potential therapeutic strategies for the treatment of brain metastases. Citation Format: Jacob P. Hoj, Benjamin J. Mayro, Ann Marie Pendergast. An actionable AXL-ABL2-TAZ signaling axis promotes lung adenocarcinoma metastasis to the brain [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr B25.