Abstract B001: Effective targeting p53 mutant pancreatic cancer by novel drug-combination strategy leveraging their DNA damage liabilities

Abstract Genetic alterations in p53 (TP53) are found in most solid malignancies, including pancreatic cancer (PANC). Mutant p53 (p53mut) contributes to cancer progression and metastasis. Existing therapeutic options for p53mut cancers are ineffective and cause toxic side effects, stressing the need for better therapies. To address these clinical problems, we developed a two-drug therapeutic strategy that selectively targets p53mut cancers. This novel strategy combines a thymidine analogue (trifluorothymidine (TFT), a component of TAS102, acting as an inducer of DNA damage), and an inhibitor of poly (ADP) ribose polymerase (PARPi) that works as an amplifier of DNA damage. Incorporation of TFT into DNA provokes post-replicative repair generating single-strand DNA break intermediates. Repair of these intermediates is assisted by PARP, while inhibition of PARP increases more lethal double-strand DNA breaks. In normal p53 wild-type (WT) cells, TAS102 and PARPi activate p53-dependent G1/S checkpoint, limiting DNA damage and promoting repair. In p53mut cells with compromised G1/S checkpoint, TAS102 and PARPi cooperate as the inducer-amplifier pair to increase lethal DNA breaks and cell death. The TAS102-PARPi strategy was validated in preclinical studies. Our first-in-human phase I study with TAS102-talazoparib regimen (NCT04511039) showed that this regimen is safe with promising efficacy. The current work investigated the mechanisms underlying the response to TAS102-PARPi regimen in p53mut cancer cells. Our data show that TAS102-PARPi induces the G2/M checkpoint mediated by ATR kinase in a p53-independent manner. ATR acts through the G2-checkpoint kinases (CHK1 and WEE1) to inactivate CDK1 and stop transition to mitosis. The transcriptome analysis showed that TAS102-PARPi treatment increased expression of Claspin and inactivated PLK1-driven mitotic pathway. Claspin is critical for activation of DNA damage and replication checkpoints by facilitating ATR-CHK1 signaling, whereas PLK1 mediates inactivation of the G2-checkpoint kinases and degradation of Claspin for normal cell cycle progression and re-entry into mitosis. Thus, the PLK1-Claspin network may play a key regulatory role in G2-checkpoint in response to TAS102-PARPi by restraining premature reentry into cell cycle of cells with unrepaired DNA. The next major question was whether TAS102-PARPi regimen can cooperate with drugs disrupting G2-checkpoint. New data show that the efficacy of TAS102-PARPi therapy is greatly enhanced by a sequential application of G2-kinase WEE1 inhibitor. Our data show that this sequential triple-drug strategy works in a synthetic-lethality manner to cause massive cell death in p53mut cancers. The triple-drug strategy greatly improved tumor control in PANC patient-derived xenografts with no signs of major toxicities to normal tissues. In summary, this study provides the scientific foundation for our novel sequential triple-drug strategy that demonstrates greater efficacy against pancreatic cancer with lower toxicity. Citation Format: Andrei Bakin, Mohammed Alruwaili, Ashley Guo, Thomas Melendy, Barbara Foster, Christos Fountzilas. Effective targeting p53 mutant pancreatic cancer by novel drug-combination strategy leveraging their DNA damage liabilities [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B001.