Editors' ChoiceDRUG RESISTANCE

Synthetic lethality with cisplatin

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Sci. Signal.  21 Aug 2018:
Vol. 11, Issue 544, eaav1294
DOI: 10.1126/scisignal.aav1294

Blocking the kinase MAST1 with lestaurtinib prevents cisplatin resistance in cancers driven by Raf-MEK signaling.

Platinum-based chemotherapy, such as cisplatin, is used to treat many types of cancers, but resistance is common, often through the activity of the kinase MEK. Cisplatin and similar agents typically function by generating intrastrand crosslinks in DNA. However, through screening and biochemical assays in various cancer cell lines, Jin et al. found that, unlike other types of platinum-based chemotherapies, cisplatin also bound directly to MEK and disrupted its interaction with its kinase cRaf. However, it did not disrupt a previously unknown interaction between MEK and the kinase MAST1. MAST1 then phosphorylated and reactivated MEK, despite the absence of cRaf, and enabled resistance to cisplatin. In cultured cells and patient-derived xenograft models, MEK reactivation after cisplatin treatment was blocked by co-application of lestaurtinib, a multikinase inhibitor that appeared to also inhibit MAST1, and thereby blocked its phosphorylation of MEK. MAST1 abundance correlated with cisplatin resistance in an array of patient tumor samples. Lestaurtinib has had mixed clinical trial results in pancreatic and prostate cancers but is FDA-approved for use in leukemia. Perhaps better success with solid tumors will result from patient selection informed by this new knowledge of the drug’s action involving MAST1, Raf-MEK signaling, and cisplatin. These findings are exciting for the prospects of overcoming cisplatin resistance, as well as for extending our understanding of the Raf-MEK pathway, which is both a common cancer driver and a path of therapeutic resistance.

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