Clinical implications of KEAP1-NFE2L2 mutations in non-small cell lung cancer.

The KEAP1-NFE2L2 pathway is an important modulator of cell homeostasis. Mutations in this pathway are common in non-small cell lung cancer (NSCLC) and have been associated with enhanced tumor growth and aggressiveness. In addition, tumors with mutations in the KEAP1-NFE2L2 pathway have been shown in pre-clinical and clinical studies to convey refractoriness to cancer-directed therapy such as radiation, chemotherapy and targeted therapy. The role of immunotherapy in this patient population is less clear and there are conflicting studies on the efficacy of immune checkpoint inhibitors in KEAP1-NFE2L2 mutant NSCLC. Here we review the current clinical evidence on several classes of anti-cancer therapeutics in KEAP1 -NFE2L2 mutant tumors. We also provide an overview of the landscape of the current clinical trials in this patient population, highlighting work being done with mTORC1/2 and glutaminase inhibition.