Molecular and protein-targeting therapies best for lung cancer with KRAS mutation

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Therapies specifically targeting the molecular profile of non-small cell lung cancer (NSCLC) with mutated KRAS, a cancer-causing protein, are the most effective treatment strategies for patients with NSCLC. These findings were presented at the American Association for Cancer Research–International Association for the Study of Lung Cancer Joint Conference on the Molecular Origins of Lung Cancer, January 6-9, 2014, in San Diego, California.

NSCLC is any type of lung cancer other than small-cell lung cancer, and is the most common type of lung cancer. NSCLC with KRAS mutations is nondruggable, and no successful targeted therapy currently exists to help patients with this form of lung cancer.

Nagla Karim, MD, PhD, principal investigator, of the University of Cincinnati (UC) Cancer Institute in Ohio and assistant professor in the Division of Hematology Oncology at the UC College of Medicine, said that researchers assessed the molecular profiling and sensitivity to the KRAS mutant lung cancer in comparison with the wild type, or nonmutant, lung cancer.

"Recent studies suggest that patients with KRAS-mutant NSCLC do not often benefit from standard systemic therapies and do not respond to epidermal growth factor receptor inhibitors, which are used to control the progression of cancer," she said.

"There is a need for therapies specifically developed for these patients, and molecular profiling has the potential to identify possible targets that might provide better treatment and innovative targeted therapy for KRAS-mutated NSCLC."

The mutation of a KRAS gene is an essential step in the development of many cancers, including NSCLC.

In the study, researchers purified RNA from banked tumor and normal lung tissue obtained from 20 patients with wild-type and 17 patients with mutant-type KRAS NSCLC tumors which were being removed in stages I and II.

"We assessed the expression of four genes involved in cell synthesis and repair, and our results show that, in mutant-type KRAS tumors, the levels of expression of several of three of the genes (BRCA1, TS, and SRC) were significantly increased in comparison to normal lung tissue," Karim said. "The expression of the same genes was significantly increased in wild-type KRAS tumors relative to their expression in normal lung.

"Interestingly, SRC expression in mutant-type KRAS tumors was decreased in comparison to wild-type KRAS tumors. These findings suggest that greater expression of the gene ERCC1 in mutant KRAS tumors might increase platinum-based chemotherapy resistance in this group of patients, whereas the greater expression of the BRCA1 in wild KRAS tumors might suggest sensitivity to taxanes, which are chemotherapy agents."

She added that this data also suggests that the combination of an approved SRC inhibitor with a TS inhibitor might improve the outcome of patients with wild-type KRAS tumors.

"These results shed new light on potentially more effective treatment strategies for patients with various types of KRAS-related non-small-cell lung cancer," she said. "We hope that these findings will lead to better therapies and improved outcomes for patients."

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