BRAF inhibitors: resistance and the promise of combination treatments for melanoma

Abstract

Identification of mutations in the gene encoding the serine/threonine-protein kinase, BRAF, and constitutive activation of the mitogen-activated protein kinase (MAPK) pathway in around 50% of malignant melanomas have led to the development and regulatory approval of targeted pathway inhibitor drugs. A proportion of patients are intrinsically resistant to BRAF inhibitors, and most patients who initially respond, acquire resistance within months. In this review, we discuss pathway inhibitors and their mechanisms of resistance, and we focus on numerous efforts to improve clinical benefits through combining agents with disparate modes of action, including combinations with checkpoint inhibitor antibodies. We discuss the merits of combination strategies based on enhancing immune responses or overcoming tumor-associated immune escape mechanisms. Emerging insights into mechanisms of action, resistance pathways and their impact on host-tumor relationships will inform the design of optimal combinations therapies to improve outcomes for patients who currently do not benefit from recent treatment breakthroughs.

Keywords: BRAF; CTLA-4; MAPK; immunotherapy; melanoma.

Figure 1. Influence of pathway resistance mechanisms on BRAF/MEK inhibitor monotherapies and combinations with immunotherapies

(A) MAPK signaling inhibition may either result in the survival of tumor cells with activated pathways such as the PI3K/AKT, or exert strong selective pressure on melanoma tumors to acquire gain-of-function mutations, methylation or high copy number loss of tumor suppressor genes such as PTEN. These can lead to increased activity of alternative pathways (e.g. PI3K/AKT), which could confer survival advantages for BRAF/MEK inhibitor-resistant melanomas. (B) The success of combinations of BRAF/MEK inhibitors with immunotherapies may also depend on activation of alternative pathways to MAPK. MAPK pathway inhibitors may potentiate an anti-tumor immune response by destroying cancer cells and the tumor microenvironment, reducing tumor-associated immunosuppressive effects, enhancing IFNγ production, T cell proliferation and MHC expression, all of which could result in tumor antigen presentation and more effective anti-tumor immune responses. All or some of these could then be further enhanced with T cell activation and Treg destruction, engendered by immune checkpoint inhibition combination or subsequent treatment (top). However, in tumors with mutations on pathway genes, including those with loss of PTEN, that support alternative activation of pathways such as the PI3K/AKT, both BRAF/MEK and checkpoint blockade inhibition as monotherapies or combinations would suffer from resistance. This may be due to impaired T cell infiltration into tumors, reduced T cell activation and expansion and loss of immuno-activatory signals (e.g. reduced IFNγ, granzyme B release). These may point to shared mechanisms of resistance for BRAF inhibitors and immunotherapies and could partly explain non-responders to combinatory or sequential BRAF/MEK inhibitor and immunotherapy treatments.