Researchers have uncovered an early survival response in ovarian cancer cells that may limit the effectiveness of widely used PARP inhibitors.
A new study from Mayo Clinic researchers reports that ovarian cancer cells can quickly switch on a survival response after treatment with PARP inhibitors. Blocking this early reaction may help these drugs work more effectively.
PARP inhibitors are widely used to treat ovarian cancer, especially in tumors with defects in DNA repair. While many patients initially respond, the benefit often fades over time as tumors become resistant. This study highlights an early mechanism that may allow cancer cells to survive treatment and suggests a way to interfere with it.
Researchers found that ovarian cancer cells rapidly activate a survival program soon after exposure to PARP inhibitors. A key player in this process is FRA1, a transcription factor that turns on genes that help cancer cells adapt and avoid cell death.
“This work shows that drug resistance does not always emerge slowly over time — cancer cells can activate survival programs very early after treatment begins,” says Arun Kanakkanthara, Ph.D., an oncology investigator at Mayo Clinic and a senior author of the study. “By targeting that early response, we may be able to improve how well existing therapies work and potentially delay or prevent resistance.”
Testing a Combination Treatment Strategy
The team explored whether brigatinib, an FDA-approved drug used for certain lung cancers, could block this survival response and boost the effects of PARP inhibitors. The drug was chosen because it targets several signaling pathways that cancer cells use to stay alive.
Results showed that combining brigatinib with a PARP inhibitor worked better than either drug alone. Notably, this benefit was observed in cancer cells but not in normal cells, suggesting the approach could be more selective and potentially safer.
Researchers also uncovered a previously unknown way brigatinib works. Instead of affecting traditional DNA repair pathways, it blocks two signaling molecules, FAK and EPHA2, which aggressive ovarian cancer cells depend on for survival. Disrupting both pathways at the same time reduced the cells’ ability to adapt and resist treatment, making them more sensitive to PARP inhibitors.
Identifying Patients Most Likely to Benefit
The study also points to a possible way to identify patients who may benefit most from this strategy. Tumors with higher levels of FAK and EPHA2 showed a stronger response to the drug combination.
Other findings suggest that ovarian cancers with elevated levels of these molecules tend to be more aggressive, which could make this approach especially useful for harder-to-treat cases.
“From a clinical perspective, resistance remains one of the biggest challenges in treating ovarian cancer,” says John Weroha, M.D., Ph.D., a medical oncologist at Mayo Clinic and a senior author of the study. “By combining mechanistic insights from Dr. Kanakkanthara’s laboratory with my clinical experience, this preclinical work supports the strategy of targeting resistance early, before it has a chance to take hold. This strategy could improve patient outcomes.”
Overall, the findings offer new insight into how ovarian cancer resists treatment and suggest a promising path for improving therapy by targeting early survival signals.
Reference: “Dual FAK and EPHA2 targeting by brigatinib tackles PARP inhibitor adaptive survival response in high-grade serous ovarian cancer” by Julie R. Duffield, Xiaonan Hou, Benjamin W. Wilson, Anjali Prasad, Iman K. McKeon-Makki, Amelia M. Huehls, Xinyan Wu, Cristina Correia, Melissa C. Larson, Fergus J. Couch, Ann L. Oberg, Scott H. Kaufmann, Larry M. Karnitz, S. John Weroha and Arun Kanakkanthara, 14 January 2026, Science Translational Medicine.
DOI: 10.1126/scitranslmed.adt8706
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.