Next batter up! Targeting cancers with KRAS-G12D mutations

Mara N Zeissig; Lauren M Ashwood; Olga Kondrashova; Kate D Sutherland

doi:10.1016/j.trecan.2023.07.010

Next batter up! Targeting cancers with KRAS-G12D mutations

Trends Cancer. 2023 Nov;9(11):955-967. doi: 10.1016/j.trecan.2023.07.010. Epub 2023 Aug 15.

Authors

Mara N Zeissig¹, Lauren M Ashwood², Olga Kondrashova², Kate D Sutherland³

Affiliations

¹ ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, 3052, Australia.
² QIMR Berghofer Medical Research Institute, Herston, 4006, Australia; The University of Queensland, Brisbane, 4072, Australia.
³ ACRF Cancer Biology and Stem Cells Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3052, Australia; Department of Medical Biology, The University of Melbourne, Melbourne, 3052, Australia. Electronic address: sutherland.k@wehi.edu.au.

PMID: 37591766
DOI: 10.1016/j.trecan.2023.07.010

Abstract

KRAS is the most frequently mutated oncogene in cancer. Activating mutations in codon 12, especially G12D, have the highest prevalence across a range of carcinomas and adenocarcinomas. With inhibitors to KRAS-G12D now entering clinical trials, understanding the biology of KRAS-G12D cancers, and identifying biomarkers that predict therapeutic response is crucial. In this Review, we discuss the genomics and biology of KRAS-G12D adenocarcinomas, including histological features, transcriptional landscape, the immune microenvironment, and how these factors influence response to therapy. Moreover, we explore potential therapeutic strategies using novel G12D inhibitors, leveraging knowledge gained from clinical trials using G12C inhibitors.

Keywords: KRAS; KRAS G12D; MRTX1133; adenocarcinoma; tumor suppressor.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma*
Humans
Mutation
Proto-Oncogene Proteins p21(ras)* / genetics
Tumor Microenvironment / genetics

Substances

Proto-Oncogene Proteins p21(ras)
KRAS protein, human