Importance: Lung cancer is the leading cause of cancer deaths worldwide, with non-small-cell lung cancer (NSCLC) constituting more than 80% of all lung cancers. Non-small-cell lung cancer is a heterogenous disease, with multiple different oncogenic driver mutations representing possible therapeutic targets. The vi-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS) represents one of the most common oncogenic driver mutations. Unfortunately, targeted therapies thus far have been unsuccessful.
Objective: To discuss current advancements in understanding the prognostic and predictive value of KRAS in NSCLC and explaining the treatment advancements in both the preclinical and clinical setting.
Evidence review: PubMed, Cochrane Library, and Google Scholar databases were searched through February 1, 2016. English-language peer-reviewed articles published between 1964 and 2016 were found using the keywords "RAS," "KRAS," "NSCLC," "synthetic lethality," "oncogenic driver mutations," "clinical trials," and "phase 3 clinical trials." Abstracts at scientific meetings were not excluded. Of 112 records idetified, 61 articles or studies were included in qualitative synthesis for this review.
Findings: The KRAS oncogenic driver mutation is noted in 15% to 25% of patients with NSCLC. While there has been limited success in inhibiting the protein directly, phase 2 and phase 3 clinical trials have demonstrated success in inhibiting downstream effectors, specifically MEK1 and/or MEK2 with selumetinib and trametinib (albeit with poor tolerability). Current clinical trials are evaluating inhibiting downstream effector pathways for improved efficacy. In the laboratory, the success of synthetic lethal approaches suggests another possible direction for future clinical trials.
Conclusions and relevance: KRAS is one of the most common oncogenic driver mutations in NSCLC, with prior attempts at direct inhibition being unsuccessful. In recent years, there has been significant advancement in the understanding of the biology of KRAS and its downstream effectors. This has translated into a multitude of important preclinical studies and clinical trials that are currently underway to find effective therapeutic drugs for KRAS mutant lung cancer. Ultimately, better therapeutics need to be engineered to arrive at RAS-driven precision medicine.