Rewiring KRAS-driven cancers through the ubiquitin-proteasome system: therapeutic opportunities with a focus on deubiquitinase.
KRAS is one of the most frequently mutated oncogenes in human cancers and plays a central role in regulating signaling pathways that control cell proliferation, survival and metabolism. Recent advances in allele-specific inhibitors, particularly those targeting KRASG12C, have demonstrated that direct pharmacological inhibition of KRAS is clinically feasible. However, the durability of therapeutic responses remains limited due to intrinsic and acquired resistance mechanisms, including secondary KRAS mutations, pathway reactivation and adaptive signaling rewiring. These challenges highlight the need for complementary strategies that extend beyond direct catalytic inhibition. The ubiquitin-proteasome system has emerged as a critical regulator of KRAS stability and signaling networks. Deubiquitinases (DUBs), which reverse ubiquitination and modulate protein turnover, have been increasingly recognized as key regulators of oncogenic signaling pathways upstream and downstream of KRAS. By influencing protein abundance, localization and signaling competence, DUBs can modulate pathway robustness and adaptive responses that contribute to therapeutic resistance. In this Review, we summarize current understanding of ubiquitin-dependent regulation in KRAS-driven cancers, focusing on DUBs and E3 ligases that directly control KRAS stability as well as those that regulate major KRAS effector pathways, including RTK-RAS, RAF-MEK-ERK and PI3K-AKT-mTOR signaling. We further discuss the therapeutic implications of DUB inhibition, its potential to overcome resistance and its relationship to emerging targeted protein degradation strategies.