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<p><i>TP53</i> is the most frequently mutated gene in high-grade serous ovarian cancer, and the majority of these mutations result in overexpression of mutant p53. Therefore, therapies that can restore the wild-type activities from p53 mutants have the potential to cause p53-mediated tumor suppressive effects. Accordingly, prior studies have shown that APR-246 can bind to specific p53 mutants, restore wild-type activities, and cause tumor suppression in cancer cell lines with hot-spot mutations. However, systematic analysis of what other p53 mutants are responsive to APR-246 is currently lacking. Here, we used a <i>TP53</i> mutagenesis library to perform functional genetic screens to identify <i>TP53</i> mutants that are sensitive to APR-246. Our studies confirm weak p53-dependent cytotoxic/cytostatic effects in OVCAR5 but not in SKOV3 and CAOV3. Further analysis identified ferroptosis sensitivity as a major determinant of APR-246 sensitivity. This agrees with the known effect of APR-246 as a disruptor of the redox system. In ferroptosis-sensitive SKOV3 and CAOV3, p53-dependent effects are not observable because APR-246 acts primarily through its induction of ferroptosis. Only in OVCAR5, which is relatively insensitive to ferroptosis compared to SKOV3 and CAOV3, do we observe a p53-dependent effect of APR-246. This study demonstrates that p53-specific effects of APR-246 are only observable in a narrow dosing window, under a specific set of conditions. Collectively, our results highlight the limitation of APR-246 as a p53-rescuing drug because of its overwhelming off-target effects on the redox system at doses that are sufficient to induce ferroptosis but insufficient to rescue mutant p53.</p><p></p>

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Unbiased assessment of APR-246 responsive p53 mutants in ovarian cancer

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月19日

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  • Anais Saunders,
  • Caili Tong,
  • Anthony N. Karnezis,
  • Gary S. Leiserowitz,
  • Jeremy Chien

摘要

TP53 is the most frequently mutated gene in high-grade serous ovarian cancer, and the majority of these mutations result in overexpression of mutant p53. Therefore, therapies that can restore the wild-type activities from p53 mutants have the potential to cause p53-mediated tumor suppressive effects. Accordingly, prior studies have shown that APR-246 can bind to specific p53 mutants, restore wild-type activities, and cause tumor suppression in cancer cell lines with hot-spot mutations. However, systematic analysis of what other p53 mutants are responsive to APR-246 is currently lacking. Here, we used a TP53 mutagenesis library to perform functional genetic screens to identify TP53 mutants that are sensitive to APR-246. Our studies confirm weak p53-dependent cytotoxic/cytostatic effects in OVCAR5 but not in SKOV3 and CAOV3. Further analysis identified ferroptosis sensitivity as a major determinant of APR-246 sensitivity. This agrees with the known effect of APR-246 as a disruptor of the redox system. In ferroptosis-sensitive SKOV3 and CAOV3, p53-dependent effects are not observable because APR-246 acts primarily through its induction of ferroptosis. Only in OVCAR5, which is relatively insensitive to ferroptosis compared to SKOV3 and CAOV3, do we observe a p53-dependent effect of APR-246. This study demonstrates that p53-specific effects of APR-246 are only observable in a narrow dosing window, under a specific set of conditions. Collectively, our results highlight the limitation of APR-246 as a p53-rescuing drug because of its overwhelming off-target effects on the redox system at doses that are sufficient to induce ferroptosis but insufficient to rescue mutant p53.