Researchers Uncover How Tumors Become Resistant to Promising p53-Targeted Therapy

Mutations in the tumor suppressor TP53 are a common cause of cancer, making the altered protein an attractive target for therapeutics. Among them, the Y220C mutation is the ninth most frequent and it creates a small crevice in the mutant protein that is not present in the wild type conformation. This druggable cavity has led to the development of small molecules such as rezatapopt that are designed to restore p53 and reactivate its normal tumor suppressor function. Rezatapopt has shown promising efficacy in early studies, but as with most targeted therapies, patients can eventually develop resistance to treatment.

A new study by Mass General Brigham investigators identifies mutations that drive clinical resistance to rezatapopt treatment. Researchers analyzed samples from patients who developed resistance to this drug and validated the underlying mechanisms using preclinical experiments, suggesting a path forward toward overcoming resistance. Results are published in Cancer Discovery.

“Our findings establish a molecular basis for why patients treated with rezatapopt may experience therapeutic failure and provide the first clinical evidence that on-target secondary TP53 mutations can lead to acquired resistance. This work galvanizes us to further investigate whether next-generation agents or combination therapies may overcome or delay the emergence of resistance,” said first author Ferran Fece de la Cruz, PhD, an instructor with the Krantz Family Center for Cancer Research at the Mass General Brigham Cancer Institute.

Seeking insight, the investigators examined blood and tumor samples from two patients enrolled in the ongoing PYNNACLE clinical trial, which is evaluating rezatapopt in participants with metastatic solid tumors with a Y220C mutation. The patients, each of whom had different types of solid tumors, both responded to treatment initially but eventually became resistant to the drug. Genetic analyses of tumor DNA revealed several new TP53 mutations that emerged during treatment—including nearly 100 new mutations in one of the patient’s samples.

To characterize how these new mutations led to drug insensitivity, the research team expressed them along with Y220C in cultured cancer cells. The researchers found that the acquired mutations fell into two main categories: those that altered p53 transcriptional activity and thus impaired its function, and others that potentially altered the Y220C pocket and disrupted rezatapopt binding.

The authors note that the former class of mutation is more likely to cause universal drug resistance to all agents within this therapeutic class, while the latter may be more drug-specific and circumvented with improved strategies, such as next-generation Y220C reactivators with a distinct mode of action. Further studies involving larger cohorts are needed to evaluate different types of acquired drug resistance.

Authorship: In addition to Ferran Fece de la Cruz, Mass General Brigham authors include Andreas Varkaris, Parasvi S Patel, Elijah W Kushner, Alvin A Morales-Giron, Sangmi Sandra Lee, Ankit Singh, Clara T Kim, Bryanna L Norden, Sara Ehnstrom, Jakob M Riedl, Jacquelyn M Curtis, Haley Barnes, Allison M Kehlmann, Nicholas Chevalier, Hitomi S Okuma, Manisha Patel, Lori Wirth, Leontios Pappas, Kayao Lau, Dejan Juric, Jessica L Hopkins, Doga C Gulhan, Aparna R Parikh and Ryan B Corcoran. Additional authors include Brendan Connell, Francis Nugent, Keelan Z Guiley, and Kevan M Shokat.

Disclosures: Corcoran has received consulting or speaking fees from Abbvie, Amgen, Array Biopharma/Pfizer, Asana Biosciences, Astex Pharmaceuticals, Astellas, Avidity Biosciences, BMS, C4 Therapeutics, Chugai, Cogent Biosciences, Daiichi-Sankyo Elicio, Erasca, Fog Pharma, Genentech, Guardant Health, Ipsen, Kinnate Biopharma, LOXO, Merrimack, Mirati Therapeutics, Natera, Navire, Nested Therapeutics, N-of-one/Qiagen, Novartis, nRichDx, Remix Therapeutics, Revolution Medicines, Roche, Syndax, Tango Therapeutics, Taiho, Theonys; holds equity in Avidity Biosciences, C4 Therapeutics, Cogent Biosciences, Erasca, Kinnate Biopharma, Interline Therapeutics, Nested Therapeutics, nRichDx, Remix Therapeutics, Revolution Medicines, and Theonys; is a co-founder, equity holder, and board member of Alterome Therapeutics and Sidewinder Therapeutics; and has received research funding from Lilly, Novartis, Relay, OnKure, Revolution Medicines, and Pfizer. Additional author disclosures can be found in the paper.

Funding: This work was supported by NIH/NCI Moonshot DRSN U54CA224068 and the Susan Eid Tumor Heterogeneity Initiative. Corcoran is also supported by the Mark J. Kusek Endowed Chair in Colorectal Cancer.

Paper cited: Fece de la Cruz, Ferran et al. “Acquired on-target alterations drive clinical resistance to p53-Y220C reactivators” Cancer Discovery DOI: 10.1158/2159-8290.CD-25-1761