KRAS Inhibitor Resistance in Lung Cancer: Mechanisms and Therapeutic Opportunities

Background/Objectives: Resistance to currently available KRAS inhibitors presents a major therapeutic challenge in non-small cell lung cancer (NSCLC). The purpose of this review is to describe the various mechanisms of resistance to KRAS inhibitors, including the activation of an epithelial-to-mesenchymal transition (EMT) program, tumor microenvironment modulation, and the rewiring of KRAS-addicted cancer cells towards other signaling pathways that promote growth and proliferation amidst KRAS inhibition. Results: Through a narrative review of recent and landmark studies in the field of KRAS inhibitor resistance, we summarize the primary non-genetic mechanisms of resistance to KRAS inhibitors as follows: receptor tyrosine kinase-mediated induction of both wild-type and mutant KRAS and the activation of several bypass signaling pathways, such as PI3K/AKT, Gas6/AXL, and YAP/TEAD/Hippo. Conclusions: We conclude that no single non-genetic driver of resistance is responsible for all cases of KRAS inhibitor resistance; rather, effective therapeutic strategies may also be informed by the tumor co-mutational status and the transcriptional phenotype of the tumor, including a mesenchymal or highly plastic cell state.