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MAPK-directed treatments and immune checkpoint inhibitors, including anti-PD-1 and CTLA-4, have increased overall survival for patients with advanced melanoma. Key challenges remain, including resistance to MAPK-directed therapy and limited immunotherapy responses in some patients. CDK4/6 pathway dysregulation in melanoma makes CDK4/6 inhibition a promising therapeutic strategy.",{"@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/advances-in-cutaneous-melanoma-therapy-the-emerging-role-of-cdk46-inhibitors/451754/",{"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/advances-in-cutaneous-melanoma-therapy-the-emerging-role-of-cdk46-inhibitors/451754.png","ImageObject",300,407,{"name":92,"@type":93},"McGucket","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-05","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are new therapies needed for advanced cutaneous melanoma?","Question",{"text":112,"@type":113},"MAPK-directed therapies can lead to resistance, and immunotherapy does not benefit every patient. 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They may also improve outcomes through combination approaches with existing therapies.","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},451754,1790946371,{"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":52,"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,"preview_page_count":4},1236954412713,"https://us-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Author Manuscript Author Manuscript Author Manuscript Author Manuscript  \n\n| | HHS Public Access\u003Cbr>Author manuscript\u003Cbr>Pharmacol Res. Author manuscript; available in PMC 2026 January 07. |\n| --- | --- |\n\nPublished in final edited form as:  \nPharmacol Res. 2025 November ; 221: 107955. doi:10.1016/j.phrs.2025.107955 .  \nAdvances in Cutaneous Melanoma Therapy: The Emerging Role of CDK4/6 Inhibitors  \nUriel Kima,e, Thomas S. McCormickb, Ankit Manglaa,c,d, Kevin D. Cooperb, Gary K. Schwartza, Akihiro Yoshidaa,b,*  \naCase Comprehensive Cancer Center, Cleveland, OH 44106, USA  \nb Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA  \nc Department of Hematology and Oncology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA  \nd University Hospitals Seidman Cancer Center, Cleveland, OH 44106, USA e Department of Dermatology, Emory University, Atlanta, GA 30322, USA  \nAbstract  \nCutaneous melanoma is a highly aggressive malignancy; however, recent advancements in targeted and immunologic therapies have significantly improved patient outcomes. MAPK-directed therapies and immune checkpoint inhibitors such as anti-PD-1 and CTLA-4 have increased overall survival for patients with advanced melanoma. Unfortunately, resistance to MAPK-directed therapies and a lack of response to immunotherapy in a subset of patients remain major challenges, underscoring the need for novel therapeutic strategies. The CDK4/6 pathway, which regulates cell cycle progression through the p16-cyclin D-CDK4/6-RB axis, is frequently dysregulated in melanoma, presenting a viable target for therapeutic intervention. CDK4/6 inhibitors (CDK4/6i), which have already demonstrated efficacy in hormone receptor-positive and human epidermal growth factor receptor 2-negative breast cancer, show promise in melanoma by inducing tumor senescence, modulating the tumor microenvironment, and enhancing patient immune responses.  \nPreclinical and translational studies suggest that CDK4/6i could be particularly effective when combined with existing therapies, including MAPK inhibitors, immune checkpoint inhibitors, and senolytic agents. Ongoing clinical trials and emerging data on combination strategies underscore the promise ofCDK4/6i as a critical component of future melanoma therapy. This review summarizes the current melanoma treatment landscape and explores the potential ofCDK4/6i in  \nThis is an open access article under the CC BY-NC-ND license ([http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/)).  \n*Corresponding author at: Department of Dermatology, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH 44106, [USA. axy234@case.edu](USA. axy234@case.edu) (A. Yoshida).  \nCRediT authorship contribution statement  \nUriel Kim: Writing – review & editing, Writing – original draft. McCormick Thomas S: Writing – review & editing. Cooper Kevin D: Supervision. Schwartz Gary K: Supervision. Akihiro Yoshida: Writing – review & editing, Writing – original draft, Validation, Supervision, Funding acquisition, Conceptualization. Ankit Mangla: Validation, Supervision.  \nDeclaration of Competing Interest  \nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this manuscript.  \nAuthor Manuscript Author Manuscript Author Manuscript Author Manuscript  \nKim et al. Page 2  \nadvancing melanoma treatment, highlighting their ability to overcome therapy resistance, improve therapeutic efficacy, and offer new strategies for patients with advanced cutaneous melanoma.  \nKeywords  \nCutaneous melanoma; CDK4/6 inhibitors; Therapy resistance; Combination therapy  \n1. Introduction  \nMelanoma is the fifth most common cancer in both men and women in the US[1], with the incidence i","cbCaib2RdjafxqAX","https://ap.wps.com/l/cbCaib2RdjafxqAX","pdf",1853309,44,"English","# Abstract\n# Keywords\n# 1. Introduction\n## Melanoma epidemiology and screening limitations\n## Systemic therapy needs in advanced melanoma\n## Historical treatment: dacarbazine and response rates","[{\"question\":\"Why are new therapies needed for advanced cutaneous melanoma?\",\"answer\":\"MAPK-directed therapies can lead to resistance, and immunotherapy does not benefit every patient. Limited efficacy in a subset of cases and ongoing survival challenges motivate novel strategies.\"},{\"question\":\"What biological rationale supports CDK4/6 inhibition in melanoma?\",\"answer\":\"The CDK4/6 pathway controls cell cycle progression through the p16-cyclin D-CDK4/6-RB axis, which is frequently dysregulated in melanoma. This dysregulation provides a viable therapeutic target.\"},{\"question\":\"What benefits do CDK4/6 inhibitors may provide in melanoma treatment?\",\"answer\":\"CDK4/6 inhibitors may induce tumor senescence, modulate the tumor microenvironment, and enhance patient immune responses. They may also improve outcomes through combination approaches with existing therapies.\"}]","Advances in Cutaneous Melanoma Therapy - The Emerging Role of CDK4/6 Inhibitors | PDF",1790735866,111]