KRAS and the reality of personalized medicine in non-small cell lung cancer

Abstract

Lung cancer is the leading cause of mortality among all cancer types worldwide. The latest available global statistics of the World Health Organization report 1.59 million casualities in 2012. Worldwide, 1 in 5 cancer deaths are caused by lung cancer. In 2016, in the United States alone, there are an estimated 224,390 new cases of lung cancer, of which 158,080 are expected to result in death, as reported by the National Cancer Institute. Non-small cell lung cancer (NSCLC), a histological subtype, comprises about 85% of all cases, which is nearly 9 out of 10 lung cancer patients. Efforts are under way to develop and improve targeted therapy strategies. Certain mutations are being clinically targeted, such as those in EGFR and ALK genes. However, one of the most frequently mutated genes in NSCLC is the Kirsten rat sarcoma viral oncogene homolog (KRAS), which is currently not targetable. Approximately 25% of all types of NSCLC tumors contain KRAS mutations, which remain as an undruggable challenge. These mutations are indicative of poor prognosis and show negative response to standard chemotherapy. Furthermore, tumors harboring KRAS mutations are unlikely to respond to currently available targeted treatments such as tyrosine kinase inhibitors. Therefore, there is a definitive, urgent need to generate new targeted therapy approaches for KRAS mutations. Current strategies have major limitations and revolve around targeting molecules upstream and downstream of KRAS. Direct targeting is not available in the clinic. Combination therapies using multiple agents are being sought. Concentrated efforts are needed to accelerate basic research and consecutive clinical trials to achieve effective targeting of KRAS.