Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation
Chaoyun Pan, … , Lingtao Jin, Sumin Kang
Chaoyun Pan, … , Lingtao Jin, Sumin Kang
Published October 1, 2019; First published August 26, 2019
Citation Information: J Clin Invest. 2019;129(10):4110-4123. https://doi.org/10.1172/JCI125963.
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Research Article Oncology Therapeutics

Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation

Abstract

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.

Authors

Chaoyun Pan, Jaemoo Chun, Dan Li, Austin C. Boese, Jie Li, JiHoon Kang, Anna Umano, Yunhan Jiang, Lina Song, Kelly R. Magliocca, Zhuo G. Chen, Nabil F. Saba, Dong M. Shin, Taofeek K. Owonikoko, Sagar Lonial, Lingtao Jin, Sumin Kang

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Figure 8

Combination of 17-AAG and lestaurtinib further inhibits MAST1 activity and cisplatin-resistant tumor growth.

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Combination of 17-AAG and lestaurtinib further inhibits MAST1 activity a...
(A and B) Combination effect of 17-AAG and lestaurtinib on expression and activity of MAST1. KB-3-1cisR and A549cisR cells were treated with 17-AAG (100 nM) and lestaurtinib (100 nM) in the presence of sublethal doses of cisplatin for 24 hours. The kinase activity of MAST1 was assessed by phospho-MEK1 S217/S221 level (A) and ADP-Glo Kinase assay (B). Effect of combinatorial treatment with 17-AAG and lestaurtinib on cell viability (C) and cisplatin sensitivity (D). (E) Combination index (CI) plots are shown for diverse cisplatin-resistant cancer cell lines. (F–H) Effect of cisplatin treatment with the combination of 17-AAG and lestaurtinib on tumor growth of lung cancer PDX mice. Mice were administered 17-AAG, lestaurtinib, and cisplatin from 28 days after xenograft. Tumor volume (F) and tumor weight (G) are shown. (H and I) The kinase activity of MAST1 in PDX tumors. Data shown are representative of 3 (A, C–E, and H) and 2 (B and I) independent biological experiments. Data are mean ± SD from 3 technical replicates for B–D and I. Error bars indicate SEM (F) and SD (G) in 5 mice/group. Statistical analysis was performed by 2-way ANOVA for F and 1-way ANOVA for all the rest. *P < 0.05; **P < 0.01; ***P < 0.005. (J) Proposed model for the stability regulation of MAST1 in human cancers. Left: Hsp90B binds to and stabilizes MAST1, which reactivates MEK1 in the absence of cRaf upon cisplatin treatment and promotes cisplatin-resistant tumor growth. Right: Loss of hsp90B induces ubiquitination of MAST1 at K317 and K545 by CHIP, which triggers its degradation. Combinatorial treatment with 17-AAG and lestaurtinib further diminishes MAST1 kinase activity and attenuates cisplatin-resistant tumor growth.