Abstract
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 BRAFV600 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. BRAFV600 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.
Highlights
Melanoma is the deadliest and most aggressive form of skin cancer, predominately arising from exposure to damaging ultraviolet radiation [1,2,3]
A better understanding of the impact of CDK4/6 inhibition (CDK4/6i) on BRAFi/MEK inhibition (MEKi)-mediated immune enhancement is critical for understanding the path forward with this combination, both as a stand-alone therapy in regard to optimal sequencing of these inhibitors, as well as their potential to be combined with immune checkpoint blockade (ICB)
Less is known about the effects of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibition on melanoma cells, an increase in MHC I in the mouse melanoma cell line B16-OVA in response to CDK4/6 inhibition has been reported, which led to enhanced T cell recognition in vitro [108], In breast cancer preclinical models and patients, induction of tumor-intrinsic interferon signaling is observed in response to CDK4/6i, which may enhance tumor immunogenicity by promoting increased secretion of T cell chemoattractants and expression of costimulatory genes [108] (Figure 3)
Summary
Melanoma is the deadliest and most aggressive form of skin cancer, predominately arising from exposure to damaging ultraviolet radiation [1,2,3]. While unrelated and mechanistically distinct, the unprecedented success of these two therapies in the clinic rapidly led to their integration as a standard-of-care treatment for melanoma patients. Despite these remarkable therapeutic advances, the overall prognosis for patients with late stage melanoma remains poor, reflecting the limitations of these therapies. Immunotherapies, on the other hand, engage the host immune response, and the immune system is arguably the only anti-cancer tool that is as adaptable as the tumor itself This is reflected in the clinical response to immune checkpoint blockade (ICB), where approximately 75% of patients who initially respond to this therapy achieve long-term sustained tumor regression [10,11,12]. The immunomodulatory activity of targeted therapies, and the potential of combined targeted therapy and ICB approaches will be discussed in this review
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