UF Health Cancer Center researchers have discovered a crucial mechanism by which a common gene mutation leads to resistance against platinum-based chemotherapy in non-small cell lung cancer. Lung cancer is the deadliest cancer that presents a major burden in North Central Florida.
Led by Zhijian Qian, Ph.D., the Pierre Chagnon Professor of Cancer Research in the UF College of Medicine, the findings suggest a novel therapeutic strategy involving drug inhibitors to reverse chemotherapy resistance. The findings were published in the Journal of Clinical Investigation.
Non-small cell lung cancer accounts for about 85% of all lung cancer cases. Despite surgery and chemotherapy combinations, survival rates remain low in part due to the development of drug resistance.
“Since platinum-based chemotherapy, such as cisplatin and carboplatin, remains a cornerstone of treatment in non-small cell lung cancer, we urgently need to identify effective targets for stopping drug resistance in these patients,” said Qian, co-leader of the UF Health Cancer Center’s Mechanisms of Oncogenesis research program.
The new study builds on previous findings from Qian’s lab about a new molecular mechanism that helps safeguard genomic stability. The researchers found that a particular signaling pathway can be activated by cancer-causing genes such as KRAS mutations.
About a quarter of patients with non-small cell lung cancer have KRAS mutations, the most frequently mutated and activated cancer-causing genes in several types of cancers.
Only two FDA-approved drugs specifically targeting one type of KRAS mutation have been developed. Other types of KRAS mutations are involved in lung cancer, though, leaving a void of effective targeted therapies.
In the new study, researchers used lung cancer cells and mouse models to show that KRAS mutations led to chemotherapy resistance by regulating RNA modification on genes related to DNA repair.
More importantly, the team found that using a drug to block the RNA modification, called m6A methylation, made the cells sensitive to chemotherapy treatment.
“This finding suggests a potential therapeutic strategy of combining drug inhibitors with platinum-based chemotherapy to overcome platinum resistance, offering new treatment avenues for lung cancer,” Qian said.
Next, the team plans to test this therapeutic approach in a broader range of mutated lung cancer cells and optimize the drug inhibitor for enhanced potency, specificity and minimal toxicity in animal models.
Fang Yu, Ph.D., a research assistant professor in Qian’s lab, was the new study’s first author. UF Health Cancer Center members Shuang Huang, Ph.D., and Lizi Wu, Ph.D., were co-authors of the study.
The study was also partially supported by the Leukemia & Lymphoma Society and UF Health Cancer Center startup funding. The UF Health Cancer Center receives crucial support for its research from the Casey DeSantis Cancer Research Act (Fla. Stat. § 381.915).
