Strategies for Molecularly Enhanced Chemotherapy to Achieve Synthetic Lethality in Endometrial Tumors with Mutant p53
Proposed synergistic mechanisms for induction of mitotic cell death in endometrial cancer cells with mutant p53. (a) In the absence of functional p53, cells rely on the p38 pathway to maintain the G2/M checkpoint via inactivating phosphorylation of Cdc2 at Tyr15. Inhibition of RTK signaling with BIBF1120 results in premature entry into mitosis, where cells are sensitive to paclitaxel and thus undergo mitotic arrest and cell death. (b) In cells with p53 GOF mutation, the p38 pathway is hyperactivated through increased MKK3 transcription by p53 GOF. Synthetic lethality can be created by combining paclitaxel with BIBF1120 and an HDACi, which presumably disrupts the association of mutant p53 with Hsp90 and leads to its degradation. Alternatively, inhibition of Wee1, downstream of hyperactivated p38, is sufficient to restore sensitivity to paclitaxel.
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