MAST1 Drives Cisplatin Resistance in Human Cancers by Rewiring cRaf-Independent MEK Activation

Publication date: Available online 19 July 2018Source: Cancer CellAuthor(s): Lingtao Jin, Jaemoo Chun, Chaoyun Pan, Dan Li, Ruiting Lin, Gina N. Alesi, Xu Wang, Hee-Bum Kang, Lina Song, Dongsheng Wang, Guojing Zhang, Jun Fan, Titus J. Boggon, Lu Zhou, Jeanne Kowalski, Cheng-Kui Qu, Conor E. Steuer, Georgia Z. Chen, Nabil F. Saba, Lawrence H. BoiseSummaryPlatinum-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.Graphical Abstract
Source: Cancer Cell - Category: Cancer & Oncology Source Type: research