Rewiring KRAS-driven cancers through the ubiquitin–proteasome system: therapeutic opportunities with a focus on deubiquitinase

Abstract

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. KRAS, a small GTPase, plays a pivotal role in cell growth and survival, and its mutations are prevalent in various cancers, including pancreatic, colorectal and lung cancers. This Review explores the development of KRAS inhibitors, highlighting the challenges due to KRAS’s ‘undruggable’ nature and the success of covalent inhibitors such as sotorasib for KRASG12C mutant cancers. The authors discuss the limitations of these inhibitors, such as resistance mechanisms that involve secondary mutations and pathway reactivation and summarize studies describing these processes. Importantly, the Review highlights the ubiquitin–proteasome system, particularly deubiquitinases, as key regulators of KRAS stability and signaling networks, providing complementary therapeutic opportunities beyond direct KRAS inhibition. The findings underscore the need for protein-level regulation and combination strategies to overcome resistance and improve the durability and efficacy of KRAS-targeted therapies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.