Immunomodulatory Effects of BRAF, MEK, and CDK4/6 Inhibitors: Implications for Combining Targeted Therapy and Immune Checkpoint Blockade for the Treatment of Melanoma
Open accessAbstract
The recent advent of targeted and immune-based therapies has revolutionized the treatment of melanoma and transformed outcomes for patients with metastatic disease. The majority of patients develop resistance to the current standard-of-care targeted therapy, dual BRAF and MEK inhibition, prompting evaluation of a new combination incorporating a CDK4/6 inhibitor. Based on promising preclinical data, combined BRAF, MEK and CDK4/6 inhibition has recently entered clinical trials for the treatment of BRAF V600 melanoma. Interestingly, while BRAF- and MEK-targeted therapy was initially developed on the basis of potent tumor-intrinsic effects, it was later discovered to have significant immune-potentiating activity. Recent studies have also identified immune-related impacts of CDK4/6 inhibition, though these are less well defined and can be both immune-potentiating and immune-inhibitory. BRAF V600 melanoma patients are also eligible to receive immunotherapy, specifically checkpoint inhibitors against PD-1 and CTLA-4. The immunomodulatory activity of BRAF/MEK-targeted therapies has prompted interest in combination therapies incorporating these with immune checkpoint inhibitors, however recent clinical trials investigating this approach have produced variable results. Here, we summarize the immunomodulatory effects of BRAF, MEK and CDK4/6 inhibitors, shedding light on the prospective utility of this combination alone and in conjunction with immune checkpoint blockade. Understanding the mechanisms that underpin the clinical efficacy of these available therapies is a critical step forward in optimizing novel combination and scheduling approaches to combat melanoma and improve patient outcomes.
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CDK4/6 inhibitors have immunomodulatory activity.
“Besides interfering cell division, CDK4/6 inhibitors also had immunomodulatory activity.”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [244]
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- Authors
- Lelliott, E. J., McArthur, G. A., Oliaro, J., & Sheppard, K. E.
- Affiliations
- The University of Melbourne (AU)
- Corresponding author
- Oliaro, Jane
- Sheppard, Karen E.
- Venue
- Frontiers in Immunology
- Publisher
- Frontiers Media SA
- Published
- 2021-05-07
- Volume
- 12
- Pages
- 661737-661737
- ISSN
- 1664-3224 (ISSN-L)
- PMC
- PMC8137893
- OpenAlex
- W3159381651
- Cited by
- 65
- References
- 147
- Citations by year
- 2026: 6 · 2025: 19 · 2024: 12 · 2023: 10 · 2022: 16 · 2021: 2
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Health and Medical Research Council
- National Breast Cancer Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Keywords
- melanoma, BRAF inhibitors, MEK inhibitors, CDK4/6 inhibitors, immunomodulation, immune checkpoint blockade, PD-1 inhibitors, CTLA-4 inhibitors, combination therapy, targeted therapy, drug resistance
- MeSH terms
- Immune Checkpoint Inhibitors, Clinical Trials as Topic, Humans, Melanoma, Skin Neoplasms, Proto-Oncogene Proteins B-raf, Cyclin-Dependent Kinase 4, Immunomodulation, Molecular Targeted Therapy
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