Post-translational modifications of KRAS: from molecular regulation to therapeutic targeting

A recent review highlights that post-translational modifications add a dynamic regulatory layer to KRAS beyond canonical GDP/GTP cycling, controlling membrane localization and trafficking, nucleotide exchange, effector engagement, protein stability, and degradation. Targeting PTM enzymes and modification-dependent regulatory networks may provide new therapeutic opportunities and strategies to overcome resistance in KRAS-driven cancers.

KRAS-driven cancer is a highly complex and dynamically regulated disease in which oncogenic signaling extends beyond genetic mutations to multiple layers of post-translational control. In a recent review published in Advanced Cancer Research, the authors provide an overview of RAS post-translational modifications, highlighting their important roles in regulating protein localization, stability, activity, and signaling output.

By modulating membrane trafficking, nucleotide cycling, effector interactions, and protein degradation, post-translational modifications add a critical regulatory layer to the canonical GDP/GTP switch of RAS. This work systematically summarizes the major types and functional consequences of RAS modifications and further discusses emerging therapeutic strategies targeting PTM-related enzymes and regulatory networks, offering new opportunities for the treatment of KRAS-driven cancers.

Key highlights include:

1. PTMs regulate RAS membrane localization, trafficking, and spatial signalling organization.
2. PTMs modulate RAS nucleotide cycling, effector engagement, protein stability, and degradation.
3. Targeting RAS PTM networks offers new therapeutic opportunities for RAS-driven cancers.

Citation: Yao N, Yang L, Zhou R, Wang J, Li X. Post-translational modifications of KRAS: from molecular regulation to therapeutic targeting. Adv. Cancer Res. 2026(3):0014, https://doi.org/10.55092/acr20260014.