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Irina Titkova, Tanya Soliman (Barts Cancer Institute, QMUL, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK)
Cancer is often caused by mutations in genes that control cell growth. One of the most commonly mutated is TP53, which normally keeps DNA stable. When TP53 is mutated, cells divide uncontrollably, making cancer more aggressive and harder to treat. Our research focuses on a specific cell cycle checkpoint that prevents cells from dividing when their DNA is tangled. This checkpoint, called the Topo2A-dependent G2 checkpoint, is lost in TP53-mutant cancer cells, forcing them to rely on a backup system, the mitotic failsafe pathway, to delay division and untangle their DNA. We studied ovarian, lung, breast, and colon cancer cells and compared them to normal cells. By silencing TP53 in normal cells, we confirmed that its loss leads to checkpoint failure. We also tested inhibitors targeting the backup system to selectively kill cancer cells. Our findings suggest that blocking Topo2A with specific inhibitors makes TP53-deficient cancer cells more vulnerable while sparing normal cells, revealing a promising strategy for cancer treatment.