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REVIEW article

Front. Cell Dev. Biol.
Sec. Cell Death and Survival
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1508577
This article is part of the Research Topic Unraveling the Role of Receptor Signaling in Tumorigenesis and Cancer Therapy View all 4 articles

CD44 Variant Exons Induce Chemoresistance by Modulating Cell Death Pathways

Provisionally accepted
Maria Yanova Maria Yanova 1Evgeniya Stepanova Evgeniya Stepanova 1Diana V. Maltseva Diana V. Maltseva 1Alexander Tonevitsky Alexander Tonevitsky 1,2*
  • 1 Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia
  • 2 Institute of Bioorganic Chemistry (RAS), Moscow, Moscow Oblast, Russia

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

    Cancer chemoresistance presents a challenge in oncology, often leading to treatment failure and disease progression. CD44, a multifunctional cell surface glycoprotein, has garnered attention for its involvement in various aspects of cancer biology. Through alternative splicing, CD44 can form isoforms with the inclusion of only standard exons, typical for normal tissue, or with the addition of variant exons, frequently expressed in cancer tissue and associated with chemoresistance. The functions of CD44 involved in regulation of cancer signaling pathways are being actively studied, and the significance of specific variant exons in modulating cell death pathways, central to the response of cancer cells to chemotherapy, begins to become apparent. This review provides a comprehensive analysis of the association of CD44 variant exons/total CD44 with clinical outcomes of patients undergoing chemotherapy. The role of CD44 variant exons v6, v9 and others with a significant effect on patient chemotherapy outcomes by means of key cellular death pathways such as apoptosis, ferroptosis and autophagy modulation is further identified, and their impact on drug resistance is highlighted. An overview of clinical trials aimed at targeting variant exon-containing isoforms is provided, and possible directions for further development of CD44-targeted therapeutic strategies are discussed.

    Keywords: CD44 variant exon 6, CD44 variant exon 9, Cancer, chemoresistance, Apoptosis, ferroptosis, Autophagy

    Received: 10 Oct 2024; Accepted: 03 Feb 2025.

    Copyright: © 2025 Yanova, Stepanova, Maltseva and Tonevitsky. 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: Alexander Tonevitsky, Faculty of Biology and Biotechnologies, National Research University Higher School of Economics, Moscow, Russia

    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.