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Identification of cancer-specific molecular targets is crucial for development of safe and efficient chemotherapy drugs. Given that mutations and deletions in the p53 gene are frequent and mostly occurs only in cancer cells, identification of compounds that selectively target cancer cells lacking wild-type p53 (wtp53) activity would significantly accelerate development of safe anti-cancer therapies. Here, we performed a high-throughput screen of a chemical library consisting of ~15,000 compounds using several p53-null or -mutated canine and human osteosarcoma cell lines as well as osteoblast cell lines carrying wtp53 as negative controls. This screening identified a new compound, namely KU0171032, as an inducer of cell death in multiple osteosarcoma cells, with minimal effects on non-transformed cells with wtp53. KU0171032 also induced apoptosis much more effectively in p53-null or -mutated cell lines as compared with those with wtp53. Depletion of wtp53 in several cancer cell lines significantly enhanced sensitivity to KU0171032 with increased DNA damage, G2/M cell cycle arrest, and caspase-3 cleavage. Moreover, KU0171032 efficiently inhibited in vivo tumor growth of cancer cells carrying mutant p53 or those knocked down for wtp53. Mechanistically, KU0171032 caused prolonged DNA damage with reduced ATM signaling and impaired DNA double-strand break repair in p53-null/mutated cells, while it caused minimal DNA damage without activation of p53 in wtp53-expressing cells unlike other chemotherapy drugs. Thus, KU0171032 targets a vulnerability of cancer cells lacking wtp53 and could be used for development of novel anti-cancer agents with minimal side effects.
Parrales, Alejandro; Nishikawa, Shigeto; Ranjan, Atul; McDonald, Peter; Roy, Anuradha; Braun, Mitchell; Schoenen, Frank; Wang, Jenna; Rogers, Steve; Broward, Melinda; Bruns, Tyce; Anant, Shrikant; Dixon, Dan; Thamm, Douglas; Weir, Scott; Neville, Kathleen; Fulbright, Joy M.; and Iwakuma, Tomoo, "Targeting Vulnerabilities Of Cancer Cells Lacking Wild-Type P53" (2021). Research at Children's Mercy Month 2021. 36.