08 May AACR25: Novel strategy for p53 mutant cancers leveraging their DNA damage response liabilities

MedicalResearch.com Interview with:

Dr. Andrei Bakin

Andrei Bakin, PhD, Associate Professor of Oncology, Department of Cancer Genetics & Genomics, Roswell Park Comprehensive Cancer Center – first author of “A novel combination immunotherapy for p53 mutant metastatic breast cancer leveraging vulnerabilities in the DNA damage response” and senior author of “Novel triple-drug combination strategy for p53 mutant cancers leveraging their DNA damage response liabilities”

Christos Fountzilas, MD, FACP, Associate Professor of Oncology, Department of Medicine, Roswell Park Comprehensive Cancer Center – and senior author of “A novel combination immunotherapy for p53 mutant metastatic breast cancer leveraging vulnerabilities in the DNA damage response”

Mohammed Alruwaili, MS, PhD, newly graduated doctoral candidate in Cancer Genetics & Genomics at Roswell Park Comprehensive Cancer Center, first author of “Novel triple-drug combination strategy for p53 mutant cancers leveraging their DNA damage response liabilities”

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Bakin: Mutated p53 is a major driver for most solid tumors and poses a significant clinical challenge. Mutant p53 contributes to cancer progression, metastasis, and poor response to therapy. The p53 protein is critical for maintenance of the human genome by regulating DNA repair and cell cycle control during DNA replication and cell division. Current therapeutic approaches for p53-mutant cancers suffer from low selectivity for p53 status and substantial off-target toxicities.

To overcome these problems, we have developed a two-drug treatment that induces DNA damage selectively within p53-mutant cancer cells. A two-drug treatment combines a thymidine analogue (TAS102) and an inhibitor of poly(ADP-ribose) polymerase (PARP). A thymidine analogue (TAS102) does not block DNA replication (synthesis), but upon incorporation into DNA, it is recognized and removed by DNA repair machinery, producing a break in one strand of DNA. In normal p53 wild-type cells, single-strand breaks activate p53 protein that stops DNA synthesis and assists in DNA repair. In p53-mutant cells, this p53 function is compromised and these cells accumulate breaks within their DNA. PARP mediates the repair of single-strand DNA breaks, while PARP inhibitors (PARPi) enhance more lethal double-strand breaks in cancer DNA. Thus, a two-drug TAS102-PARPi therapy works as an inducer-amplifier pair that induces double-strand breaks selectively in p53-mutant cancer cells.

In the current work, we provide evidence for effective control of p53-mutant cancers by a sequential triple-drug strategy that combines a two-drug TAS102-PARPi therapy with a delayed sequential application of the WEE1-kinase inhibitor. We demonstrate that a two-drug TAS102-PARPi therapy induces double-strand DNA breaks in p53-mutant cells, and these cells stop their cell division and attempt to repair DNA. We identified the WEE1 kinase as a key protein in stopping cell division. We further show that inhibition of WEE1 permits these p53-mutant cells (with damaged DNA) to proceed to cell division, resulting in cell death. Importantly, delaying exposure to a WEE1 inhibitor allows normal p53 wild-type cells to repair DNA, reducing the impact in normal tissues. This sequential triple-drug inducer-amplifier-terminator approach demonstrated high efficacy in p53-mutant colorectal and pancreatic ductal adenocarcinoma cancer models, with no major toxicities in mice.

MedicalResearch.com: Would these markers help guide prognosis or therapy?

Dr. Fountzilas: Yes, our sequential triple-drug inducer-amplifier-terminator strategy represents a promising approach for treatment of p53-mutant cancers. At present, the two-drug TAS102-PARPi strategy is being tested in a clinical trial for colorectal cancer patients. The preliminary data show that the two-drug combination is well-tolerated, and efficacy is very promising. The current work showed that a sequential triple-drug inducer-amplifier-terminator strategy exhibits much greater efficacy in control of p53-mutant cancers.

MedicalResearch.com: What should readers take away from your report?

Mohammed Alruwaili: A sequential triple-drug inducer-amplifier-terminator strategy is highly effective against p53-mutant solid cancers, such as breast, colorectal, and pancreatic cancers. The treatment is selective for p53-mutant cancers and did not show significant toxicities in normal tissues.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Dr. Fountzilas: Future research will be directed to translate our findings to a clinical trial. We have already initiated contacts with pharmaceutical companies for the development of a clinical protocol.

MedicalResearch.com: Is there anything else you would like to add? Any disclosures?

Dr. Bakin said:  The research was funded by NIH/NCI and the Roswell Park Alliance Foundation. A patent application describing the invention has been filed.

AACR 2025 presentation:

Mohammed M. Alruwaili, Aidan Mazierski, Erica Norris, Kyeong Beom Jo, Yanqi Guo, Priyanka Rajan, Henry Withers, Thomas Melendy, Christos Fountzilas, Andrei Bakin; Abstract 5991: Novel triple-drug combination strategy for p53 mutant cancers leveraging their DNA damage response liabilities. Cancer Res 15 April 2025; 85 (8_Supplement_1): 5991. https://doi.org/10.1158/1538-7445.AM2025-5991

More information:

• Duffy MJ, Synnott NC, O’Grady S, Crown J. Targeting p53 for the treatment of cancer. Seminars in Cancer Biology. 2022;79:58-67. doi:10.1016/j.semcancer.2020.07.005

• Wang Z, Strasser A, Kelly GL. Should mutant TP53 be targeted for cancer therapy? Cell Death & Differentiation. 2022;29(5):911-920. doi:10.1038/s41418-022-00962-8

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Last Updated on May 8, 2025 by Marie Benz MD FAAD