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Updated: May 8, 2026
A 3D Organotypic Melanoma Spheroid Skin Model
Published on: May 18, 2018
Trametinib for the treatment of melanoma
1Division of Hematology and Oncology, University of Colorado Cancer Center, Aurora, Colorado, USA. Antonio.Jimeno@UCDenver.edu.
Abstract:
Advanced melanoma traditionally has had poor prognosis with limited, modestly effective and relatively toxic systemic treatment options like cytotoxic chemotherapy (dacarbazine) and immunomodulating agents (high-dose interleukin-2 and ipilimumab) which have response rates of 6-20%. With the identification of BRAF mutations found to be present in 50% of melanomas and the clinical success of serine/threonine-protein kinase B-raf inhibitors the prognostic landscape of melanoma has changed considerably. Vemurafenib and dabrafenib have been at the forefront of antimelanoma-targeted agents with a tolerable side effect profile and efficacy that compared well with the standard chemotherapy. These characteristics have led to the regulatory approval of both agents for the treatment of melanoma. However, these agents are not curative and have a short life span primarily due to rapidly occurring drug resistance. More recently, mitogen-activated protein kinase kinase (MEK) inhibitors have been found to have strong anticancer activity independently as well as when combined with other agents like B-raf inhibitors due to their activity downstream of RAF. Preclinical data and limited clinical data suggest that MEK inhibitors may be a component of effective therapy for a broad spectrum of cancers with other oncogenic drivers.
Insights
Targeted therapies like BRAF and MEK inhibitors have improved advanced melanoma treatment. While effective, drug resistance necessitates exploring combination strategies for better outcomes.
Area of Science:
- Oncology
- Dermatology
- Pharmacology
Background:
- Advanced melanoma historically presented a poor prognosis with limited, toxic systemic treatments.
- Cytotoxic chemotherapy and immunomodulating agents offered low response rates (6-20%).
- The discovery of BRAF mutations in 50% of melanomas revolutionized treatment paradigms.
Purpose of the Study:
- To review the evolution of advanced melanoma systemic therapy.
- To highlight the impact of BRAF inhibitors and the emergence of MEK inhibitors.
- To discuss the potential of MEK inhibitors in overcoming drug resistance.
Main Methods:
- Literature review of systemic treatment options for advanced melanoma.
- Analysis of clinical trial data for BRAF and MEK inhibitors.
- Evaluation of preclinical and clinical data on combination therapies.
Main Results:
- BRAF inhibitors (vemurafenib, dabrafenib) demonstrated improved efficacy and tolerability over chemotherapy.
- Targeted BRAF inhibition significantly altered the prognostic landscape of melanoma.
- Drug resistance remains a significant challenge, limiting the long-term efficacy of BRAF inhibitors.
- Mitogen-activated protein kinase kinase (MEK) inhibitors show promise independently and in combination therapy.
Conclusions:
- BRAF inhibitors represent a major advance in melanoma treatment but are not curative due to resistance.
- MEK inhibitors, acting downstream of RAF, offer a potential strategy to overcome resistance.
- Further investigation into MEK inhibitors, alone or in combination, is warranted for advanced melanoma and other cancers.
