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. Jin et al. show that cisplatin dissociates cRaf from MEK1 to inhibit the MAPK pathway and identify MAST1 as a main cisplatin resistance driver that replaces cRaf to reactivate the MAPK pathway. They further show that inhibition of MAST1 by the multi-kinase inhibitor lestaurtinib restores cisplatin sensitivity.
- MAPK signaling
- cisplatin resistance
- dual-kinase inhibitor
- microtubule-associated serine/threonine kinase 1
- platinum-based cancer therapy
ASJC Scopus subject areas
- Cancer Research