KRAS-Mutated Lung Cancer

Abstract

A mutation in the Kirsten rat sarcoma virus transforming protein (KRAS) is the most common genomic driver identified in patients with lung adenocarcinoma. It is a key component of the PI3K and MAPK pathways and is an important regulator of cell proliferation and survival. Tobacco use and mutations in KRAS are strongly correlated and co-mutation of p53 or STK11 is common. KRAS is affected by upstream signaling from a variety of tyrosine kinase inhibitors including the epidermal growth factor receptor (EGFR) and ERBB2. Affected patients have a higher risk of death than with other driver mutations and, despite dozens of clinical trials attempting to find a specific inhibitor that is effective in this population, it has been a difficult drug target. There is substantial experience attempting to treat KRAS-mutated lung adenocarcinoma with the use of RAS/RAF multikinase inhibitors as well as inhibitors of both upstream and downstream proteins important in RAS signaling. We review the disappointing results from these clinical trials in lung cancer. However, more recently, there appears to be some improvement in outcome with immune checkpoint inhibitors in these patients.