Houston – Researchers have identified a potential new weakness in an aggressive form of breast cancer,offering hope for more targeted therapies. A study published today in Science Translational Medicine details how blocking two specific proteins, ATR and PKMYT1, can trigger cell death in triple-negative breast cancers lacking the Rb1 gene. The findings,from MD Anderson Cancer Center at the university of Texas,build on growing understanding of “synthetic lethality” – exploiting vulnerabilities created by a tumor’s own genetic defects – and could rapidly translate to clinical benefit,as several relevant inhibitors are already in FDA Fast Track trials.
A new study published today in Science Translational Medicine details a potential therapeutic vulnerability in patients with an aggressive subtype of triple-negative breast cancer. Understanding these vulnerabilities is crucial for developing more effective, targeted treatments for this challenging disease.
Researchers at the MD Anderson Cancer Center at the University of Texas, led by Khandan Keyomarsi, Ph.D., professor of experimental radio-oncology, found that simultaneously inhibiting ATR and PKMYT1 triggers a specific type of cell death in breast cancer models lacking Rb1.
Using genomic profiling, proteomics, and patient-derived xenografts, the team discovered that loss of Rb1 – a gene vital for normal cell division – disrupts DNA repair processes. This forces tumor cells to rely on pathways dependent on ATR and PKMYT1 to survive, creating a weakness that could be selectively targeted.
“This is a groundbreaking discovery,” said Keyomarsi. “Tumors deficient in Rb1 don’t 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 potentially identify patients who might benefit from a completely different therapeutic strategy.”
The study demonstrates that blocking both ATR and PKMYT1 – two proteins necessary for maintaining genomic stability during cell division – induces cell death in Rb1-deficient breast cancers. By blocking these two repair pathways, the treatment overwhelms the cancer cells’ ability to correct DNA errors, leading to catastrophic DNA damage, apoptosis (programmed cell death), tumor shrinkage, and improved survival in preclinical models.
Rb1 normally prevents uncontrolled cell division and helps maintain the integrity of the genome. When Rb1 is lost, cells accumulate DNA errors more quickly and are prone to malignant transformation. These tumors also resist CDK4/6 inhibitors because the treatment relies on an intact Rb1 pathway to halt the cell cycle.
However, the same mechanism that allows mutations to occur more easily also creates a vulnerability. While DNA mutations can lead to cancer development, cancer cells also need to replicate. If they produce too many mutations during replication, they can no longer function. Intentionally triggering this process through inhibition is known as synthetic lethality.
By inhibiting ATR and PKMYT1 – both important for repairing DNA mutations – this strategy causes a buildup 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 promising aspects of this research is its potential for near-term clinical application. Several ATR and PKMYT1 inhibitors are already in clinical trials and have received Fast Track designation from the Food and Drug Administration (FDA).
The MYTHIC Phase I trial, also led by researchers at MD Anderson, is currently testing the combination in patients with 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 combined strategy, our study also shows that Rb1 deficiency predicts sensitivity to other DNA-damaging therapies, such as chemotherapy and radiation,” said Keyomarsi. “Incorporating Rb1 status into clinical decision-making could help design more effective and personalized treatment plans for these patients.”
