Targeting Cancer Cells Before They Develop Treatment-Resistance

Scientists may have found a way to prevent treatment-resistance in patients with non-small cell lung cancer (NSCLC).

Patients who undergo chemotherapy often respond initially to treatment, but will later develop drug resistance that can turn fatal. The American Cancer Society estimates that NSCLC accounts for 85% of all lung cancer cases in the United States.

In a study published in Cell Reports, investigators found a 35-gene signature that can identify tumor cells most likely to develop treatment-resistance.

“Cancer relapse after chemotherapy poses a major obstacle to treating lung cancer, and resistance to chemotherapy is a big cause of that treatment failure,” said co-author Dr John Minna. “These findings provide new insights into why resistance develops and how to overcome it.”

For the study, investigators examined mouse and cellular models of NSCLC. They used long-term on/off drug cycles to develop a series of cellular models of progressive tumor resistance to standard chemotherapy that ranges from very sensitive to highly sensitive.

The investigators identified genes commonly altered during the development of treatment resistance across multiple cell line and mouse models. The findings showed a 35-gene signature that indicated a higher genetic likelihood of chemo-resistance.

“It’s like a fingerprint for resistance,” said senior author Dr Elisabeth D. Martinez.

The resistance biomarker was then compared using genetic profiles from human tumors obtained from the National Cancer Institute lung cancer Specialized Programs of Research Excellence (SPORE) database, which contains information on patient outcomes and who had been treated with a dual-drug chemotherapy.

“Previous studies have shown that up to 70% of those cancers develop resistance to standard therapy, such as the platinum-taxane 2-drug combo that is often given,” Dr Martinez said.

The investigators found that the genetic fingerprint for resistance correlated with cancer relapse in patients from the SPORE database with NSCLC.

The results of the study showed that as NSCLC cells developed a stronger resistance to chemotherapy, they also progressively produced higher amounts of the enzymes JumonjiC lysine demethylases, which facilitated resistance by changing the genes expression.

“Cancer cells use these enzymes to change, or reprogram, gene expression in order to survive the toxic stress of the chemotherapy,” Martinez said. “By changing the expression of genes, the tumor cells can adapt and survive the toxins.

Based on the findings, the investigators wanted to examine the effects of 2 JumonjiC inhibitors: JIB-04 and GSK-J4.

“I believe this is the first report of NSCLC tumors taking advantage of multiple JumonjiC enzymes to reprogram gene expression in order to survive chemotoxic stress,” Dr Martinez said. “In addition, and this is the most fascinating part: Dr Dalvi found that greater chemotherapy resistance defines a new susceptibility to the JumonjiC inhibitor. The cancer cells develop a new Achilles’ heel that we can hit.”

The findings indicate that because chemo-resistant cancer cells rely on JumonjiC enzymes to survive, inhibiting this enzyme will restore cellular vulnerability to treatment.

“We think these JumonjiC inhibitors have the potential to be used to treat tumors once they become resistant to standard therapies, or to prevent resistance altogether,” Martinez said. “In our experiments these inhibitors appear to be much more potent in killing cancer cells than normal cells.”