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Cancer Cell. 2018 Aug 13;34(2):315-330.e7. doi: 10.1016/j.ccell.2018.06.012. Epub 2018 Jul 19.

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

Author information

1
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA.
2
Department of Neuroscience, Morehouse School of Medicine, Atlanta, GA 30310, USA.
3
Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA.
5
School of Pharmacy, Fudan University, Shanghai 201203, China.
6
Department of Biostatistics and Bioinformatics, Emory University School of Public Health, Atlanta, GA, USA.
7
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322, USA.
8
Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA.
9
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, GA 30322, USA. Electronic address: smkang@emory.edu.

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.

KEYWORDS:

MAPK signaling; cisplatin resistance; dual-kinase inhibitor; lestaurtinib; microtubule-associated serine/threonine kinase 1; platinum-based cancer therapy

Comment in

PMID:
30033091
PMCID:
PMC6092215
[Available on 2019-08-13]
DOI:
10.1016/j.ccell.2018.06.012
[Indexed for MEDLINE]

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