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Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward
Journal article   Open access   Peer reviewed

Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward

Ioannis A. Voutsadakis
Current issues in molecular biology, Vol.47(6), 454
06/01/2025
DOI: 10.3390/cimb47060454
PMCID: PMC12192106
PMID: 40699853
url
https://doi.org/10.3390/cimb47060454View
Published (Version of record) Open Access

Abstract

Targeting the cell cycle has become a focus of cancer research bearing impressive results with the introduction of CDK4/6 inhibitors in the treatment of ER-positive/HER2-negative breast cancers. However, no definitive benefit in other cancers has been observed. In gastrointestinal cancers, despite preclinical studies pinpointing positive effects on cancer inhibition in pre-clinical models, no positive clinical trials have been published with CDK4/6 inhibitors. Several biomarkers have been proposed in breast cancers, where the field is more advanced, and include up-regulations of the inhibited kinases CDK4 and CDK6 and their partner cyclin D as well as the main target of phosphorylation, RB. Up-regulation of Cyclin E, an E2F1/RB regulated gene, also arises as a marker of CDK4/6 inhibition resistance. Signaling from receptor tyrosine kinase pathways through KRAS/BRAF/MEK and PI3K/AKT/mTOR are also implicated in feedback CDK4/6 activation and inhibitors resistance. In gastrointestinal cancers, some of these biomarkers have also proven valuable in predicting sensitivity to CDK4/6 inhibitors and would lead markers to guide clinical development. Modulation of the tumor microenvironment, where immune cells are prominent components, arises as a feature of CDK4/6 inhibition and could be harnessed in therapeutic combinations.
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