| Literature DB >> 30033091 |
Lingtao Jin1, Jaemoo Chun1, Chaoyun Pan1, Dan Li1, Ruiting Lin1, Gina N Alesi1, Xu Wang1, Hee-Bum Kang1, Lina Song2, Dongsheng Wang1, Guojing Zhang1, Jun Fan3, Titus J Boggon4, Lu Zhou5, Jeanne Kowalski6, Cheng-Kui Qu7, Conor E Steuer1, Georgia Z Chen1, Nabil F Saba1, Lawrence H Boise1, Taofeek K Owonikoko1, Fadlo R Khuri1, Kelly R Magliocca8, Dong M Shin1, Sagar Lonial1, Sumin Kang9.
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.Entities:
Keywords: MAPK signaling; cisplatin resistance; dual-kinase inhibitor; lestaurtinib; microtubule-associated serine/threonine kinase 1; platinum-based cancer therapy
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Year: 2018 PMID： 30033091 PMCID： PMC6092215 DOI： 10.1016/j.ccell.2018.06.012
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743