A new study published by Mayo Clinic researchers suggests that ovarian cancer cells quickly activate a survival response after PARP inhibitor treatment, and blocking this early response may make this class of drugs work better.
PARP inhibitors are a common treatment for ovarian cancer and can be especially effective in cancers with impaired DNA repair. However, many tumors eventually stop responding, even when the drugs initially show results. The new research identifies a way cancer cells may survive PARP inhibitor treatment early on, and it points to a potential strategy to block that response.
In the study, researchers found that ovarian cancer cells rapidly activate a pro-survival program after exposure to PARP inhibitors. A key driver of this response is FRA1, a transcription factor that helps turn on genes that allow cancer cells to 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."
The research team tested whether brigatinib, an FDA-approved drug currently used to treat certain lung cancers, could block this survival response and enhance the effects of PARP inhibitors. Brigatinib was selected because of its ability to inhibit multiple signaling pathways involved in cancer cell survival.
The results showed that combining brigatinib with a PARP inhibitor was more effective than either treatment alone. Importantly, this effect was seen only in cancer cells, not in normal cells, suggesting the potential for a more targeted and safer treatment approach.
Surprisingly, the researchers discovered that brigatinib helps in a completely new way. Rather than acting through traditional DNA repair pathways, brigatinib shuts down two key signaling molecules, FAK and EPHA2, that aggressive ovarian cancer cells rely on to survive. Blocking both signals at once weakened the cancer cells' ability to adapt and resist treatment, leaving them far more vulnerable to PARP inhibitors.
The researchers also found a potential clue for identifying which patients might benefit most from this treatment. Tumors with higher levels of the signaling molecules FAK and EPHA2 responded better to the drug combination. Other data suggest that ovarian cancers with high levels of these molecules are often more aggressive, highlighting the promise of this approach 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."
This research sheds new light on how ovarian cancer evades treatment, and it points to a promising strategy for improving patient outcomes.
