[PDF][PDF] MAST1 drives cisplatin resistance in human cancers by rewiring cRaf-independent MEK activation

L Jin, J Chun, C Pan, D Li, R Lin, GN Alesi, X Wang… - Cancer cell, 2018 - cell.com
L Jin, J Chun, C Pan, D Li, R Lin, GN Alesi, X Wang, HB Kang, L Song, D Wang, G Zhang…
Cancer cell, 2018cell.com
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 …
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.
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