Proteomic Perspectives on KRAS-Driven Cancers and Emerging Therapeutic Approaches

TL;DR

This paper reviews proteomic changes caused by KRAS mutations in cancer and explores new therapies and resistance mechanisms.

Contribution

The paper provides a proteomics-informed perspective on KRAS-driven cancers and emerging therapeutic strategies.

Findings

KRAS mutations are linked to significant proteomic alterations and disrupted signaling pathways in cancers like PDAC, CRC, and NSCLC.

Allele-specific proteome signatures and PTMs of KRAS influence functional networks and tumorigenesis.

Recent KRASG12C inhibitors show promise, but resistance remains a major clinical challenge.

Abstract

As one of the most frequently mutated oncogenes, the KRAS protein has long been a target of intense therapeutic interest. In this review, we summarize and discuss the current knowledge of proteomic alterations associated with oncogenic KRAS mutations, with particular emphasis on allele-specific proteome signatures and the roles of post-translational modifications (PTMs) of KRAS in modulating functional networks. Furthermore, we highlight recent therapeutic advances targeting KRAS variants and examine emerging resistance mechanisms from a proteomics-informed perspective.

KRAS mutations are implicated in approximately 23% of all human malignancies, with particularly high prevalence in pancreatic ductal adenocarcinoma (PDAC) (~92%), colorectal cancer (CRC) (~49%), and non-small cell lung cancer (NSCLC) (~35%). The recent approval of the KRASG12C-specific inhibitors for NSCLC represents a pivotal advancement in KRAS-targeted therapy. Nevertheless, the emergence of intrinsic and acquired resistance to KRAS-targeted therapies poses a significant clinical obstacle to targeting KRAS, which necessitates a deeper understanding of the resistance mechanisms. Recent progress in proteomic studies has enabled comprehensive profiling of the proteomic alterations driven by KRAS mutations, offering valuable insights into the disrupted KRAS interactome, aberrant signaling pathways and dysregulated cellular processes contributing to tumorigenesis. This review discusses current knowledge on proteomic alterations associated with oncogenic KRAS mutations, with particular focus on allele-specific proteome signatures and the roles of post-translational modifications (PTMs) of KRAS in modulating the functional networks. Furthermore, we highlight recent therapeutic advances targeting KRAS variants and discuss emerging resistance mechanisms from a proteomics-informed perspective.

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