TY - JOUR AU - Pan, Chaoyun AU - Chun, Jaemoo AU - Li, Dan AU - Boese, Austin C. AU - Li, Jie AU - Kang, JiHoon AU - Umano, Anna AU - Jiang, Yunhan AU - Song, Lina AU - Magliocca, Kelly R. AU - Chen, Zhuo G. AU - Saba, Nabil F. AU - Shin, Dong M. AU - Owonikoko, Taofeek K. AU - Lonial, Sagar AU - Jin, Lingtao AU - Kang, Sumin T1 - Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation PY - 2019/10/01/ AB - Microtubule-associated serine/threonine kinase 1 (MAST1) is a central driver of cisplatin resistance in human cancers. However, the molecular mechanism regulating MAST1 levels in cisplatin-resistant tumors is unknown. Through a proteomics screen, we identified the heat shock protein 90 B (hsp90B) chaperone as a direct MAST1 binding partner essential for its stabilization. Targeting hsp90B sensitized cancer cells to cisplatin predominantly through MAST1 destabilization. Mechanistically, interaction of hsp90B with MAST1 blocked ubiquitination of MAST1 at lysines 317 and 545 by the E3 ubiquitin ligase CHIP and prevented proteasomal degradation. The hsp90B-MAST1-CHIP signaling axis and its relationship with cisplatin response were clinically validated in cancer patients. Furthermore, combined treatment with a hsp90 inhibitor and the MAST1 inhibitor lestaurtinib further abrogated MAST1 activity and consequently enhanced cisplatin-induced tumor growth arrest in a patient-derived xenograft model. Our study not only uncovers the regulatory mechanism of MAST1 in tumors but also suggests a promising combinatorial therapy to overcome cisplatin resistance in human cancers. JF - The Journal of Clinical Investigation JA - J Clin Invest SN - 0021-9738 DO - 10.1172/JCI125963 VL - 129 IS - 10 UR - https://doi.org/10.1172/JCI125963 SP - 4110 EP - 4123 PB - The American Society for Clinical Investigation ER -