A Sequential Triple-Drug Strategy for Selective Targeting of p53-Mutant Cancers

The tumor suppressor TP53 gene (p53) is mutated in most human malignancies but existing treatment options are largely ineffective, lack selectivity, and cause toxic side effects. To address these clinical problems, we have developed a two-drug treatment that induces lethal DNA damage and G2-arrest in p53 mutant cancer cells. Here, we present a triple-drug therapeutic strategy that combines our two-drug regimen with a G2-checkpoint kinase inhibitor. The two-drug treatment with TAS102 plus PARP inhibitor (PARPi) acts as an inducer-amplifier pair to induce DNA double-strand breaks (DSBs) and a prolonged G2-arrest specifically in p53 mutant cells. Subsequent inhibition of the G2-checkpoint kinases, such as WEE1 or ATR, releases these G2-arrested cells into mitosis, leading to cell death. The delayed administration of a G2-kinase inhibitor provides p53 wild-type cells with time to repair DNA, thereby minimizing toxicity to normal tissues. This sequential triple-drug strategy exhibited robust efficacy in preclinical models of colorectal and pancreatic cancers. Together, our findings illustrate a promising inducer-amplifier-terminator triple-drug strategy for targeting p53 mutant malignancies.