Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers.

Abstract

Simple SummaryWhile KRAS is a driver oncogene, tumor cells can acquire mutant KRAS independency by activating pathways that functionally substitute for mutant KRAS. These KRAS-independent tumor cells exhibit a mesenchymal phenotype, readily primed for potential metastasis. The activation of YAP and/or RSK-mTOR pathways and mutations in LKB1, KEAP1, and/or NRF2 are associated with mutant KRAS autonomy. These alterations rewire survival signaling and metabolic processes originally governed by mutant KRAS. The presence of KRAS-independent cells is associated with the heterogeneity of KRAS mutant cancers, as well as variable responses to therapies. Notably, KRAS G12C-specific inhibitors appear to be effective only in tumors dependent on mutant KRAS for their survival. Therefore, determining KRAS dependency will be critical for selecting patients who should be treated with mutant-specific inhibitors. Furthermore, elucidating underlying mechanisms of KRAS autonomy is crucial towards developing optimal treatment strategies for KRAS-independent tumors.Activating mutations in KRAS are present in 25% of human cancers. When mutated, the KRAS protein becomes constitutively active, stimulating various effector pathways and leading to the deregulation of key cellular processes, including the suppression of apoptosis and enhancement of proliferation. Furthermore, mutant KRAS also promotes metabolic deregulation and alterations in the tumor microenvironment. However, some KRAS mutant cancer cells become independent of KRAS for their survival by activating diverse bypass networks that maintain essential survival signaling originally governed by mutant KRAS. The proposed inducers of KRAS independency are the activation of YAP1 and/or RSK-mTOR pathways and co-mutations in SKT11 (LKB1), KEAP1, and NFE2L2 (NRF2) genes. Metabolic reprogramming, such as increased glutaminolysis, is also associated with KRAS autonomy. The presence or absence of KRAS dependency is related to the heterogeneity of KRAS mutant cancers. Epithelial-to-mesenchymal transition (EMT) in tumor cells is also a characteristic phenotype of KRAS independency. Translationally, this loss of dependence is a cause of primary and acquired resistance to mutant KRAS-specific inhibitors. While KRAS-dependent tumors can be treated with mutant KRAS inhibitor monotherapy, for KRAS-independent tumors, we need an improved understanding of activated bypass signaling pathways towards leveraging vulnerabilities, and advancing therapeutic options for this patient subset.