Clinical Implications of KEAP1-NFE2L2 Mutations in NSCLC

The KEAP1-NFE2L2 pathway is an important modulator of cell homeostasis. Mutations in this pathway are common in NSCLC and have been associated with enhanced tumor growth and aggressiveness. In addition, tumors with mutations in the KEAP1-NFE2L2 pathway have been reported in preclinical 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 anticancer therapeutics in KEAP1-NFE2L2–mutant tumors. Furthermore, we provide an overview of the landscape of the current clinical trials in this patient population, highlighting the work being done with mTORC1, mTORC2, and glutaminase inhibition.