Abstract 4082: Hsp90B protects MAST1 from CHIP-mediated ubiquitination and degradation providing cisplatin resistance

Microtubule-associated serine/threonine kinase 1 (MAST1) plays a key role in cisplatin resistance of human cancers. However, the mechanism underlying MAST1 regulation remains elusive. We identified the hsp90B as a direct MAST1 binding partner essential for its stabilization via a proteomics screen. Targeting hsp90B in cancer cells sensitizes cisplatin treatment mainly through MAST1 destabilization. Mechanistically, hsp90B protects MAST1 from ubiquitination at lysine 317 and 545 by the E3 ubiquitin ligase CHIP and prevents proteasomal degradation. The role of the hsp90B-MAST1-CHIP signaling axis in cisplatin resistance was clinically validated in cancer patients. Furthermore, a combination of hsp90 inhibitor and MAST1 inhibitor lestaurtinib further inhibited MAST1 activity and consequently potentiated the cisplatin effect in a patient-derived xenograft model. Our study not only reveals the mechanism of MAST1 regulation in tumors but also demonstrates a promising combinatorial therapy to overcome cisplatin resistance in human cancers. Citation Format: Chaoyun Pan, Jie Li, Austin Boese, Sumin Kang. Hsp90B protects MAST1 from CHIP-mediated ubiquitination and degradation providing cisplatin resistance [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 4082.