Researchers identify Rb1 as a predictive biomarker for a new therapeutic strategy in some breast cancers

(Press-News.org) Preclinical study identifies Rb1 deficiency as key therapeutic vulnerability in a subset of breast cancers resistant to standard CDK4/6 inhibitors Drugs that may exploit this vulnerability are already in clinical trials Rb1-deficient cancers represent nearly 40% of triple-negative and estrogen receptor–positive tumors, which together account for roughly 20% of all breast cancers Rb1 status could also serve as an important predictive biomarker for other treatment strategies HOUSTON, DECEMBER 24, 2025 ― A new study published today in Science Translational Medicine by researchers at The University of Texas MD Anderson Cancer Center details a therapeutic vulnerability in  patients with an aggressive subtype of triple-negative breast cancer.

Led by Khandan Keyomarsi, Ph.D., professor of Experimental Radiation Oncology, the study shows that simultaneous inhibition of ATR and PKMYT1 triggers a type of cell death in Rb1deficient breast cancer models.

Using genomic profiling, proteomics and patient-derived xenografts, the researchers found that loss of Rb1 – a gene important for normal cell division – disrupts DNA repair processes and forces tumor cells to rely on ATR and PKMYT1 dependent pathways for survival, creating a vulnerability that can be selectively targeted.

“This is a breakthrough discovery,” Keyomarsi said. “Rb1-deficient tumors do not respond to CDK4/6 inhibitors because they depend on Rb1 to regulate cell division. But that same deficiency makes them vulnerable to ATR and PKMYT1 inhibition. We can now identify patients who may benefit from an entirely different therapeutic strategy.”

What is the major finding of this study on ATR and PKMYT1 co-inhibition?
The study demonstrates that simultaneously inhibiting ATR and PKMYT1 – two proteins required for maintaining genomic stability during cell division – induces cell death in Rb1-deficient breast cancers. By blocking both repair pathways, the treatment overwhelms the cancer cell’s ability to correct DNA errors, leading to catastrophic DNA damage, apoptosis, tumor shrinkage and improved survival in preclinical models.

How does Rb1 deficiency create a vulnerability if it also indicates resistance?
Rb1 normally prevents uncontrolled cell division and helps maintain genomic integrity. When Rb1 is lost, cells accumulate DNA errors more rapidly and become prone to malignant transformation. These tumors also resist CDK4/6 inhibitors because the therapy depends on an intact Rb1 pathway to halt the cell cycle.

The same mechanism that allows mutations to more easily occur also creates the vulnerability. While DNA mutations can lead to cancer development, cancer cells also need to replicate, and if they build  too many mutations as they replicate, they can no longer function. Using an inhibitor to intentionally cause this to happen is what’s known as synthetic lethality.

By inhibiting ATR and PKMYT1 – two proteins that are also important for repairing mutations in DNA – this strategy causes and overload of mutations, leading to cell death and ultimately tumor shrinkage. In this study, targeting these pathways led to tumor shrinkage and increased overall survival in preclinical models.

What are the next steps for bringing this discovery to the clinic?
One of the most noteworthy aspects of  this study is its near-term clinical relevancy. Several ATR and PKMYT1 inhibitors already are in clinical trials and have received fast-track designation from the FDA.

The Phase I MYTHIC Trial, which is also being led by MD Anderson researchers, is one example of a trial already testing the combination for certain mutations in solid tumors. The current findings could directly inform the development of Rb1-based biomarker strategies to identify patients most likely to benefit from dual ATR/PKMYT1 inhibition.

“Beyond this combination strategy, our study also shows that Rb1 deficiency predicts sensitivity to other DNA-damaging therapies, such as chemotherapy and radiation,” Keyomarsi said. “Incorporating Rb1 status into clinical decision-making could help tailor more effective, personalized treatment plans for these patients.”

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This study was supported by the National Cancer Institute (CA255960, CA223772), the Cancer Prevention and Research Institute of Texas (CPRIT RP180712), and the National Institutes of Health UPWARDS Training Program (R25CA240137). A full list of collaborating authors and their disclosures can be found with the paper.

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