KRAS Profiling in Non-Squamous NSCLC

Potentials from molecular profiling to identify possible targets that might provide better treatment and innovative targeted therapy for KRAS-mutated NSCLC

The researchers from the University of Cincinnati Cancer Institute have found in a small molecular profiling study that the most effective treatment strategy for KRAS-mutant non-small cell lung cancer (NSCLC) would be combined targeting of oncogenic KRAS in addition to other therapeutic agents specific to the molecular profile of the tumour. The findings were presented in a poster session at the American Association for Cancer Research–International Association for the Study of Lung Cancer (AACR-IASLC) Joint Conference on the Molecular Origins of Lung Cancer (6-9 January, 2014, San Diego, USA).

KRAS mutated NSCLC is non-druggable, and no successful targeted therapy currently exists to help patients with this form of lung cancer. Recent studies suggest that these patients failed to benefit from standard systemic therapies and do not respond to epidermal growth factor receptor (EGFR) inhibitors.

The study: KRAS mutant NSCLC in comparison with the wild type tumours

Nagla Karim, assistant professor in the Division of Hematology/Oncology at the University of Cincinnati College of Medicine, was a principal investigator on this study. The mutation of a KRAS gene is an essential step in the development of many cancers, including NSCLC. In this study, the researchers assessed the molecular profiling and sensitivity to the KRAS mutant NSCLC in comparison with the wild type tumours.

They purified RNA from banked tumours and normal lung tissue obtained from 20 patients with wild-type and 17 patients with mutant-type KRAS NSCLC tumours which were being removed in stages I and II. By reverse transcriptase-real time polymerase chain reaction (RT-PCR) they assessed expression of four genes involved in DNA synthesis and repair including thymidylate synthase (TS), BRCA1, ECCR1 and RAP80, and the proto-oncogene SRC.

The results

The results show that in mutant-type KRAS tumours, the levels of expression of ERCC1, TS and SRC genes were significantly increased in comparison to normal lung tissue. The expression of the BRCA1, TS and SRC genes was significantly increased in wild-type KRAS tumours relative to their expression in normal lung. Interestingly, SRC expression in mutant-type KRAS tumours was decreased in comparison to wild-type KRAS tumours.

These findings suggest that greater expression of the gene ERCC1 in mutant KRAS tumours might increase platinum-based chemotherapy resistance in this group of patients, whereas the greater expression of the BRCA1 in wild KRAS tumours might suggest sensitivity to taxanes. The data also suggests that the combination of SRC inhibitor with a TS inhibitor, such as pemetrexed, might improve the outcome of patients with wild-type KRAS tumours.

These results shed new light on potentially more effective treatment strategies for patients with KRAS-related NSCLC. The researchers hope that these findings will lead to better therapies and improved outcomes for the patients.