Preclinical study finds Rb1 loss as a key vulnerability in CDK4/6-resistant breast cancers, with drugs already in trials.
A newly published study in Science Translational Medicine by researchers at The University of Texas MD Anderson Cancer Center reveals an important therapeutic vulnerability in a particularly aggressive subset of triple-negative breast cancer (TNBC).
The study identifies the loss of the RB1 tumor suppressor gene as a central biological weakness in tumors that do not respond to standard CDK4/6 inhibitor–based therapies, which are commonly used to control cancer cell proliferation.
TOP INSIGHT
A new study has found a major vulnerability in nearly 40% of triple-negative and ER+ #breastcancers. These “Rb1-deficient” tumors represent about 20% of all breast cancer cases. While they often resist standard treatments, researchers now have a clear target to fight them.
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RB1 Deficiency Drives Resistance While Creating New Drug Targets
The researchers show that RB1 deficiency fundamentally disrupts normal cell-cycle regulation, reshaping how cancer cells grow and respond to treatment. This disruption not only explains why certain TNBC tumors develop resistance to CDK4/6 inhibitors, but also exposes alternative molecular dependencies that could be therapeutically exploited. By mapping these altered pathways, the study provides a clearer understanding of the mechanisms driving treatment failure in this hard-to-treat cancer subtype.
Importantly, the findings point toward more personalized, biomarker-driven treatment strategies for patients with RB1-deficient tumors. Identifying RB1 loss could help guide clinicians toward alternative therapeutic approaches better suited to these cancers, potentially improving outcomes for patients who currently face limited options. Overall, the research advances understanding of therapy resistance in breast cancer and lays the groundwork for developing more precise, targeted interventions for aggressive TNBC.
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.”
Dual ATR–PKMYT1 Inhibition Triggers Lethal DNA Damage in RB1-Deficient Breast Cancer
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.
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.
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.”
Source-Eurekalert