Lung cancer drug shows promise in overcoming ovarian cancer drug resistance

SCIENTISTS at Mayo Clinic in the United States have uncovered an early survival mechanism that helps ovarian cancer cells evade PARP inhibitor therapy and, a potential way to stop it. Their new study reveals that tumors can switch on protective pathways almost immediately after treatment begins, which may explain why many patients eventually stop responding to these widely used drugs.

PARP is a type of enzyme involved in many functions of the cell, including the repair of DNA damage, according to the U.S.-based National Cancer Institute (NCI) said.

PARP inhibitors are a mainstay in ovarian cancer care, particularly for tumors with defective DNA repair systems. While they often work well at first, resistance commonly develops. The researchers found that this loss of sensitivity may start far earlier than previously thought, driven by rapid cellular changes that allow cancer cells to adapt.

The study shows that ovarian cancer cells activate a pro-survival gene programme shortly after exposure to PARP inhibitors. Central to this response is FRA1, a transcription factor that switches on genes linked to stress tolerance and continued growth, enabling the cells to escape treatment-induced death.

“This research challenges the idea that resistance only appears after long-term drug exposure,” said an oncology investigator at Mayo Clinic and senior author of the study, Dr Arun Kanakkanthara. “If we can interrupt that early survival response, we may be able to strengthen current therapies and delay resistance.”

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To counter this effect, the team tested brigatinib, an FDA-approved drug used in certain lung cancers, to see whether it could block the newly identified pathway. Brigatinib was chosen because it targets several signaling routes that cancer cells depend on for survival.

When used alongside a PARP inhibitor, it significantly improved treatment effectiveness compared with either drug alone. Notably, the combination was toxic to cancer cells but spared normal cells, suggesting a more selective and potentially safer therapeutic approach.

Further analysis revealed that brigatinib works in an unexpected way. Instead of affecting DNA repair directly, it disables two key signaling proteins, FAK and EPHA2, which aggressive ovarian cancer cells rely on. By shutting down both pathways, the drug leaves cancer cells unable to mount their usual defense against PARP inhibition.

The researchers also identified a possible marker to guide future treatment. Tumors with elevated levels of FAK and EPHA2 responded best to the drug combination. These molecules are often associated with more aggressive disease, raising the possibility that this strategy could be especially useful for hard-to-treat patients.

“Resistance is one of the greatest obstacles in ovarian cancer therapy,” said a Mayo Clinic medical oncologist and senior author of the study, Dr John Weroha. “This work suggests that targeting resistance from the very start could improve outcomes by stopping it before it becomes established.”

Overall, the findings offer new insight into how ovarian cancer adapts to treatment and highlight a promising combination strategy that could enhance the durability of existing therapies.