1. MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation.
- Author
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Jin L, Chun J, Pan C, Li D, Lin R, Alesi GN, Wang X, Kang HB, Song L, Wang D, Zhang G, Fan J, Boggon TJ, Zhou L, Kowalski J, Qu CK, Steuer CE, Chen GZ, Saba NF, Boise LH, Owonikoko TK, Khuri FR, Magliocca KR, Shin DM, Lonial S, and Kang S
- Subjects
- Animals, Cell Line, Tumor, Drug Resistance, Neoplasm, Enzyme Activation, Female, Humans, Mice, Antineoplastic Agents pharmacology, Cisplatin pharmacology, MAP Kinase Kinase 1 physiology, Microtubule-Associated Proteins physiology, Protein Serine-Threonine Kinases physiology, Proto-Oncogene Proteins c-raf physiology
- Abstract
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., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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