Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward
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 p...
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MDPI AG
2025-06-01
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| Series: | Current Issues in Molecular Biology |
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| author | Ioannis A. Voutsadakis |
| author_facet | Ioannis A. Voutsadakis |
| author_sort | Ioannis A. Voutsadakis |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0f49095bfb3f49c686d659f823e9c323 |
| institution | OA Journals |
| issn | 1467-3037 1467-3045 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | MDPI AG |
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| series | Current Issues in Molecular Biology |
| spelling | doaj-art-0f49095bfb3f49c686d659f823e9c3232025-08-20T02:24:37ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452025-06-0147645410.3390/cimb47060454Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move ForwardIoannis A. Voutsadakis0Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USATargeting 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.https://www.mdpi.com/1467-3045/47/6/454CDK4CDK6RBE2F1abemaciclibpalbociclib |
| spellingShingle | Ioannis A. Voutsadakis Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward Current Issues in Molecular Biology CDK4 CDK6 RB E2F1 abemaciclib palbociclib |
| title | Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward |
| title_full | Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward |
| title_fullStr | Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward |
| title_full_unstemmed | Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward |
| title_short | Development of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward |
| title_sort | development of cdk4 6 inhibitors in gastrointestinal cancers biomarkers to move forward |
| topic | CDK4 CDK6 RB E2F1 abemaciclib palbociclib |
| url | https://www.mdpi.com/1467-3045/47/6/454 |
| work_keys_str_mv | AT ioannisavoutsadakis developmentofcdk46inhibitorsingastrointestinalcancersbiomarkerstomoveforward |