Impact of CD44 alternative splicing on the response to anticancer drugs

The transmembrane glycoprotein CD44, a marker of cancer stem cells (CSCs), plays a role in tumor initiation, progression, and multidrug resistance (MDR) phenotype in many cancers. The functional diversity of CD44 is determined by alternative splicing, which generates variant isoforms (CD44v) from the single gene CD44. This transcriptomic plasticity is not only structural but also governs tumor cell metabolic adaptations, phenotypic heterogeneity, and sensitivity to anticancer therapies. The balance between the standard isoform (CD44s) and CD44v is frequently altered in malignant cells and has been mechanistically linked to the acquisition of malignant and CSC characteristics, such as self-renewal capacity and activation of mechanisms of chemoresistance, which include changes in the expression or function of drug transporters, enhanced antioxidant defense, metabolic reprogramming, and upregulation of survival/apoptosis signaling pathways. Moreover, differential CD44v interactions with the tumor microenvironment facilitate cell migration, matrix adhesion, and metastatic dissemination. Given the pivotal role of CD44v in tumor aggressiveness and patient prognosis, several therapeutic strategies have been investigated, including small-molecule inhibitors, nucleic acid-based approaches to modulate splicing or expression, monoclonal antibodies, and peptide inhibitors. The safety profile of therapies targeting CD44v remains poorly characterized. However, the adverse effects could be closely tied to CD44's physiological functions in normal tissues, and consequently, could include disruption of immune cell recruitment, alteration of inflammatory responses, impairment of tissue repair, and induction of skin toxicity. Defining CD44v functions at a mechanistic level will support the rational development of isoform-tailored interventions and biomarkers to anticipate and counteract chemoresistance, thereby improving clinical outcomes.