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 Rb1-deficient 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 cancer cells to rely on ATR- and PKMYT1-dependent survival pathways, creating a vulnerability that can be selectively targeted.
This is an important discovery. Rb1-deficient tumors do not respond to CDK4/6 inhibitors because they depend on Rb1 to regulate cell division. But this same deficiency makes them vulnerable to ATR and PKMYT1 inhibition. We can now identify patients who may benefit from a completely different treatment strategy.”
Khandan Keyomarsi, Ph.D., Professor of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center
What is the main finding of this study about ATR and PKMYT1 co-inhibition?
The study shows that simultaneous inhibition of ATR and PKMYT1 – two proteins required to maintain 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 repair 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 implies 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 are also resistant to CDK4/6 inhibitors because therapy depends on an intact Rb1 pathway to arrest the cell cycle.
The same mechanism that allows mutations to occur more easily also creates the vulnerability. While DNA mutations can lead to the development of cancer, cancer cells also need to reproduce, and if they make too many mutations as they reproduce, they can no longer function. Using an inhibitor to purposely cause this to happen is what is known as synthetic lethality.
By inhibiting ATR and PKMYT1 – two proteins that are also important for DNA mutation repair – this strategy also causes mutation overload, leading to cell death and eventual tumor shrinkage. In this study, targeting these pathways led to tumor shrinkage and increased overall survival in preclinical models.
What are the next steps in bringing this discovery to the clinic?
One of the most remarkable aspects of this study is its short-term clinical relevance. Several ATR and PKMYT1 inhibitors are already in clinical trials and have received fast-track designation from the FDA.
The Phase I MYTHIC Trial, also led by MD Anderson researchers, is an 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,” Keiomarsi said. “Incorporating Rb1 status into clinical decision-making could help tailor more effective, personalized treatment plans for these patients.”
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