Proteostasis Reprogramming in Mutant KRAS-Driven Cancers

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ABSTRACT KRAS is one of the most frequently mutated genes in human cancers. Despite advances in the development of inhibitors that directly target mutant KRAS and the FDA approval of KRASG12C inhibitor sotorasib for KRASG12C- mutant non-small cell lung cancer (NSCLC), cancer cell adaptation and resistance to KRAS inhibitors are almost inevitable and remains a major challenge that limits their clinical benefits. Our preliminary data establish proteostasis reprogramming as an essential mechanism that mediates tumor resistance to KRAS inhibitor. Inactivation of oncogenic KRAS rapidly downregulates both the heat shock response (HSR) and IRE1a branch of the unfolded protein response (UPR). However, only IRE1a is selectively reactivated in KRASi-resistant tumors. Genetic or pharmacologic suppression of IRE1a substantially sensitizes KRASG12C-mutant tumors to sotorasib, leading to complete and durable responses in preclinical NSCLC and pancreatic cancer models. Mechanistically, we found that oncogenic KRAS-MAPK signaling promotes IRE1a protein stability through direct ERK-IRE1a interaction. In contrast, multiple mechanisms of resistance to KRASi, including reactivated ERK and hyperactivated AKT, converge to re-activate IRE1a in resistant tumors. These findings provide a framework to seek biological insight into the proteostasis reprogramming in KRAS-mutant cancers, and to further explore the effects of pharmacological inhibition of proteostasis reprogramming as an anti-tumor approach for KRAS-mutant cancers. We hypothesize that IRE1a-mediated proteostasis reprogramming facilitates tumor resistance to oncogenic KRAS inhibition and that multiple resistance pathways converge with IRE1a to restore proteostasis and promote therapy resistance to KRAS inhibitors. This proposal will determine the molecular mechanisms of differential IRE1a regulation in response to mutant KRAS inhibition (Aim 1), define proteostasis machinery crosstalk between HSR and UPR in KRAS-mutant cancers (Aim 2), and evaluate the therapeutic efficacy of targeting proteostasis reprogramming to overcome KRASi resistance in KRAS-mutant cancers (Aim 3). Accomplishing these aims will establish the biological significance and biochemical basis of oncogenic signaling regulated proteostasis network in KRAS-mutant human cancers, leading to development of more effective and well-tolerated therapeutic strategy to reverse KRASi resistance and bypass the on-target toxicity of targeting multiple resistance signaling pathways.