Josephin Domain Containing 2 (JOSD2) Inhibition as Pan-KRAS-Mutation-Targeting Strategy for Colorectal Cancer

KRAS is the most common mutated oncogenes in colorectal cancer (CRC), yet effective therapeutic strategies for targeting multiple KRAS-mutations remained challenging. The prolonged protein stability of KRAS mutants contribute to their robust tumor-promoting effects, but the underlying mechanism is elusive. Herein by screening deubiquitinases (DUBs) siRNA library, we identified Josephin domain containing 2 (JOSD2) functions as a potent DUB that regulates the protein stability of KRAS mutants. Mechanistically, JOSD2 directly interacted with and stabilized KRAS variants across different mutants, by reverting their proteolytic ubiquitination; while KRAS mutants reciprocally inhibited the catalytic activity of CHIP, a bona fide E3 ubiquitin ligase for JOSD2, thus forming a JOSD2/KRAS positive feedback circuit that significantly accelerated KRAS-mutant CRC growth. Inhibition of JOSD2 by RNA interference or its pharmacological inhibitor promoted the polyubiquitination and proteasomal degradation of KRAS mutants, and preferentially impeded the growth of KRAS-mutant CRC including patient-derived cells/xenografts/organoids (PDCs/PDXs/PDOs) over that harboring wild-type KRAS. Collectively, this study not only revealed the crucial roles of JOSD2/KRAS positive feedback circuit in KRAS-mutant CRC, but also provides a rationale to target JOSD2 as the promising pan-KRAS-mutation-targeting strategy for the treatment of a broad population of CRC patients with KRAS variant across different mutant types.