1. MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation.
- Author
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Jin, Lingtao, Chun, Jaemoo, Pan, Chaoyun, Li, Dan, Lin, Ruiting, Alesi, Gina N., Wang, Xu, Kang, Hee-Bum, Song, Lina, Wang, Dongsheng, Zhang, Guojing, Fan, Jun, Boggon, Titus J., Zhou, Lu, Kowalski, Jeanne, Qu, Cheng-Kui, Steuer, Conor E., Chen, Georgia Z., Saba, Nabil F., and Boise, Lawrence H.
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CISPLATIN , *CANCER cells , *CANCER patients , *RNA interference , *THREONINE - Abstract
Summary Platinum-based chemotherapeutics represent a mainstay of cancer therapy, but resistance limits their curative potential. Through a kinome RNAi screen, we identified microtubule-associated serine/threonine kinase 1 (MAST1) as a main driver of cisplatin resistance in human cancers. Mechanistically, cisplatin but no other DNA-damaging agents inhibit the MAPK pathway by dissociating cRaf from MEK1, while MAST1 replaces cRaf to reactivate the MAPK pathway in a cRaf-independent manner. We show clinical evidence that expression of MAST1, both initial and cisplatin-induced, contributes to platinum resistance and worse clinical outcome. Targeting MAST1 with lestaurtinib, a recently identified MAST1 inhibitor, restores cisplatin sensitivity, leading to the synergistic attenuation of cancer cell proliferation and tumor growth in human cancer cells and patient-derived xenograft models. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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