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REVIEW article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1441938
This article is part of the Research Topic Targeting Cellular Signalling Pathways for Disease Therapy: The Potential of Cellular Reprogramming and Protein Kinase Inhibitors View all 4 articles

Mediating Kinase Activity in Ras-Mutant Cancer: Potential for An Individualised Approach?

Provisionally accepted
Fiona Healy Fiona Healy 1*Amy L. Turner Amy L. Turner 1Vanessa Marensi Vanessa Marensi 2,3David J. MacEwan David J. MacEwan 1
  • 1 Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom
  • 2 Chester Medical School, Chester, United Kingdom
  • 3 Department of Biochemistry, Cell and Systems Biology, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, United Kingdom

The final, formatted version of the article will be published soon.

    It is widely acknowledged that there is a considerable number of oncogenic mutations within the Ras superfamily of small GTPases which are the driving force behind a multitude of cancers. Ras proteins mediate a plethora of kinase pathways, including the MAPK, PI3K and Ral pathways. Since Ras was considered undruggable until recently, pharmacological targeting of pathways downstream of Ras has been attempted to varying success, though drug resistance has often proven an issue.Nuances between kinase pathway activation in the presence of various Ras mutants are thought to contribute to the resistance, however, the reasoning behind activation of different pathways in different Ras mutational contexts is yet to be fully elucidated.Indeed, such disparities often depend on cancer type and disease progression.However, we are in a revolutionary age of Ras mutant targeted therapy, with directtargeting KRAS-G12C inhibitors revolutionising the field and achieving FDA-approval in recent years. However, these are only beneficial in a subset of patients.Approximately 90% of Ras-mutant cancers are not KRAS-G12C mutant, and therefore raises the question as to whether other distinct amino acid substitutions within Ras may one day be targetable in a similar manner, and indeed whether better understanding of the downstream pathways these various mutants activate could further improve therapy. Here, we discuss the favouring of kinase pathways across an array of Ras-mutant oncogenic contexts and assess recent advances in pharmacological targeting of various Ras mutants. Ultimately, we will examine the utility of individualised pharmacological approaches to Ras-mediated cancer.

    Keywords: Cancer, kinase, Mutation, Ras, signalling, targeted therapy

    Received: 31 May 2024; Accepted: 06 Sep 2024.

    Copyright: © 2024 Healy, Turner, Marensi and MacEwan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Fiona Healy, Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, L69 7BE, United Kingdom

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.