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The review highlights how CDK4/6 inhibitors are widely used in combination with hormone receptor antagonists for ER+/HER2− breast cancer, with substantial clinical benefit. It also summarizes how ongoing research seeks new combination approaches and extends CDK4/6 inhibitor use to additional diseases, while acknowledging key limitations such as heterogeneous cellular responses and the rapid emergence of drug resistance. Recent findings are emphasized, including resistance mechanisms that extend beyond cell-cycle arrest to affect cell metabolism, autophagy, and the tumor microenvironment. The article provides an integrated overview of how CDK4/6 inhibitors suppress cancer and how these insights may support more effective, potentially personalized treatment strategies.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/breaking-cancers-momentum-cdk46-inhibitors-and-the-promise-of-combination-therapy-review/365933/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/breaking-cancers-momentum-cdk46-inhibitors-and-the-promise-of-combination-therapy-review/365933.png","ImageObject",300,407,{"name":92,"@type":93},"Fahsai","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the primary anticancer mechanism of CDK4/6 inhibitors described in the review?","Question",{"text":112,"@type":113},"CDK4/6 inhibitors target CDK4/6 complexes to induce cell cycle arrest in the G1 phase, thereby suppressing cancer cell proliferation.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Why are CDK4/6 inhibitors emphasized over earlier generations of CDK inhibitors?",{"text":117,"@type":113},"Earlier broad-spectrum CDK inhibitors were limited by poor selectivity and dose-limiting toxicities, while CDK4 and CDK6 inhibitors reduce off-target toxicity while maintaining efficacy.",{"name":119,"@type":110,"acceptedAnswer":120},"What factors contribute to resistance to CDK4/6 inhibitors?",{"text":121,"@type":113},"Resistance can arise from adaptive changes in cell cycle regulatory pathways, activation of bypass signaling routes, and interactions with immune-related components in the tumor microenvironment.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},365933,1790314716,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},549768702563,"https://ap-avatar.wpscdn.com/avatar/8000c4aa63b76e948b?x-image-process=image/resize,m_fixed,w_180,h_180&k=1786536092046926083","Review  \nBreaking Cancer’s Momentum: CDK4/6 Inhibitors and the Promise of Combination Therapy  \nYanbiao Liu 1, Seohyun Park 1 and Yan Li 1,2, *  \nAcademic Editor: Christos Papadimitriou Received: 10 May 2025  \nRevised: 5 June 2025  \nAccepted: 7 June 2025  \nPublished: 11 June 2025  \nCitation: Liu, Y.; Park, S.; Li, Y. Breaking Cancer’s Momentum:  \nCDK4/6 Inhibitors and the Promise of Combination Therapy. Cancers 2025, 17, 1941. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cancers17121941  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 School of Science, Auckland University of Technology, Auckland 1010, New Zealand; [gww8665@autuni.ac.nz](gww8665@autuni.ac.nz) (Y.L.); [stella.park@aut.ac.nz](stella.park@aut.ac.nz) (S.P.)  \n2 Maurice Wilkins Centre, Auckland 1010, New Zealand  \n* [Correspondence: yan.li@aut.ac.nz](Correspondence: yan.li@aut.ac.nz)  \nSimple Summary: CDK4/6 inhibition is a crucial therapy for targeting cell cycle dysregulation in cancer treatment. The combination of CDK4/6 inhibitors and hormone receptor antagonists has demonstrated remarkable clinical efficacy in treating ER+/HER2 − breast cancer patients. Recent studies have uncovered new resistance mechanisms and their unexpected effects beyond cell cycle arrest. In this review, we describe the status of CDK4/6 inhibition in cancer treatment, focusing on mechanisms by which drug resistance developsand recent progress in combination therapies.  \nAbstract: CDK4/6 inhibition represents a new generation of cancer therapies, targeting CDK4/6 complexes to induce cell cycle arrest in the G1 phase. These inhibitors have been widely used in combination with hormone receptor antagonists for treating ER+/HER2 − breast cancer, achieving significant clinical success. Building on this progress, ongoing research explores novel combination therapies and expands the application of CDK4/6 inhibitors to other diseases. However, challenges remain, including variable cellular responses and the rapid development of drug resistance. Recent studies have uncovered new resistance mechanisms and their unexpected effects on cell metabolism, autophagy, and the tumor microenvironment beyond cell cycle arrest. This review provides a comprehensive overview of the mechanisms by which CDK4/6 inhibitors combat cancer and explores their potential for more effective and personalized treatment strategies.  \nKeywords: CDK 4/6 inhibitor; cancer treatment; combination therapy  \n1. Introduction  \nCell division is fundamental for the growth, development, and reproduction of living organisms. The cell cycle refers to a series of precisely regulated biological processes that occur between the completion of one cell division and the beginning of the next. In eukaryotic cells, the progression of the cell cycle is rigidly controlled by cyclins and cyclindependent kinases (CDKs) . Cyclins are a large family of proteins expressed periodically, originally discovered by R. Timothy Hunt in 1982 [1] . They are classified into different types, each functioning at specific stages of the cell cycle by activating CDKs. CDKs comprise a large family of serine/threonine kinases with evolutionarily conserved regulation of the cell cycle in eukaryotic cells [2] . Each cyclin exists as an inactive monomer and forms a cyclin–CDK complex with its cognate CDK, which in turn phosphorylates substrates onserine and threonine residues to drive cell cycle progression. Such kinases are frequently overactivated in cancer cells to sustain proliferation, disrupting cell number homeostasis and normal tissue architecture.  \nThe inhibition of CDKs has emerged as a promising therapeutic strategy for cancer treatment","cbCaidfLrwswq2li","https://ap.wps.com/l/cbCaidfLrwswq2li","pdf",3005664,23,"English","# Introduction\n## Cell cycle regulation in cancer\n## From broad CDK inhibition to CDK4/6 specificity\n## Resistance mechanisms and emerging effects","[{\"question\":\"What is the primary anticancer mechanism of CDK4/6 inhibitors described in the review?\",\"answer\":\"CDK4/6 inhibitors target CDK4/6 complexes to induce cell cycle arrest in the G1 phase, thereby suppressing cancer cell proliferation.\"},{\"question\":\"Why are CDK4/6 inhibitors emphasized over earlier generations of CDK inhibitors?\",\"answer\":\"Earlier broad-spectrum CDK inhibitors were limited by poor selectivity and dose-limiting toxicities, while CDK4 and CDK6 inhibitors reduce off-target toxicity while maintaining efficacy.\"},{\"question\":\"What factors contribute to resistance to CDK4/6 inhibitors?\",\"answer\":\"Resistance can arise from adaptive changes in cell cycle regulatory pathways, activation of bypass signaling routes, and interactions with immune-related components in the tumor microenvironment.\"}]","Breaking Cancer’s Momentum - CDK4/6 Inhibitors and the Promise of Combination Therapy - Review | PDF",1790162982,58]