Compound found that reduces resistance to cancer treatment

In many patients with cancer, radiation and genotoxic treatment is not enough because tumor cells can develop resistance to these interventions. But now researchers have identified how these treatments trigger this mechanism of resistance—and they’ve discovered how to inhibit this mechanism to make tumor cells more vulnerable to treatment, according to a study published September 3, 2015 in Nature Communications.

Prior research had already shown that that RAF proteins—a family of kinases that regulate cellular signaling—control resistance to therapies. “We discovered an undescribed role for RAF and learned precisely how it occurs in a broad range of cancers,” said lead author Sunil Advani, MD, assistant professor in the Department of Radiation Medicine and Applied Sciences at the University of California San Diego (UCSD), in La Jolla, CA.

The researchers found that treatment of tumors with ionizing radiation or genotoxic drugs triggers a kinase-independent mechanism that tumor cells use for DNA repair and therapeutic resistance. Once they determined this, the researchers sought to impede this pathway by developing a new RAF inhibitor—a drug-like compound called KG5.

In experiments with KG5 in mice, the researchers were able to successfully reverse tumor cells’ resistance to both radiotherapy and certain genotoxic drugs.

“We are taking the tumor’s defenses away by targeting this pathway. By developing this drug, we have the potential to enhance radiation sensitivity of cancer while sparing healthy tissue,” said principal investigator, David Cheresh, PhD, Distinguished Professor of Pathology and associate director for Innovation and Industry Alliances at UCSD Moores Cancer Center. “This drug increases the DNA-damaging effects of radiation and certain chemotherapies. We essentially get more anti-tumor activity with less radiation or chemotherapeutic drug. This allows us to see the anti-tumor effect while reducing terrible side effects. We have seen this in pancreatic, brain, and lung cancer cells both in cell culture and in tumors growing in mice.”

The hope is to increase survival rates among a broad range of patients with highly aggressive cancers, Dr. Advani said. “For patients with aggressive cancers, there may be no good options left. Armed with this new approach, our goal is utilize such a drug to improve the clinical outcomes of some of the most widely used anti-cancer therapies,” he said.