Page 21 - Read Online

Conroy et al. Cancer Drug Resist 2021;4:543-58 Cancer
DOI: 10.20517/cdr.2021.07
Drug Resistance

Review Open Access

Emerging RAS-directed therapies for cancer

2,3
1,#
1,#
Michael Conroy , Darren Cowzer , Walter Kolch , Austin G. Duffy 1
1
Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 7, Ireland.
2
Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin 4, Ireland.
3
Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
#
Authors contributed equally.
Correspondence to: Prof. Austin G. Duffy, Department of Medical Oncology, Mater Misericordiae University Hospital, Dublin 7,
Ireland. E-mail: austinduffy@mater.ie
How to cite this article: Conroy M, Cowzer D, Kolch W, Duffy AG. Emerging RAS-directed therapies for cancer. Cancer Drug
Resist 2021;4:543-58. https://dx.doi.org/10.20517/cdr.2021.07
Received: 26 Jan 2021 First Decision: 24 Feb 2021 Revised: 8 Mar 2021 Accepted: 16 Mar 2021 Available online: 8 Apr 2021

Academic Editor: Godefridus J. Peters Copy Editor: Yue-Yue Zhang Production Editor: Yue-Yue Zhang

Abstract
RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers represent
a major burden of human disease. Though these oncogenes were discovered decades ago, recent years have seen
major advances in understanding of their structure and function, including the therapeutic and prognostic
significance of diverse isoforms. Targeting of these mutations has proven difficult, despite some successes with
inhibition of RAS effector signalling. More recently, direct RAS inhibition has been achieved in a trial setting. While
this has yet to be translated to everyday clinical practice, this development carries much promise. This review
summarizes the diverse approaches that have been taken to RAS inhibition and then focuses on the most recent
developments in direct inhibition of KRAS(G12C).

Keywords: Ras, pancreatic, targeted, signalling, isoform, erk, inhibition

INTRODUCTION
Since the discovery of RAS oncogenes as the transforming genes of oncogenic retroviruses in the 1960s,
[1,2]
great advances have been made in our understanding of their structure and role in human cancer. The three
RAS genes, Kirsten rat sarcoma viral oncogene homolog (K-RAS), neuroblastoma RAS viral (v-ras)
oncogene homolog (N-RAS) and Harvey rat sarcoma viral oncogene homolog (H-RAS), are the most

© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.

www.cdrjournal.com