MEK Inhibitors in the Treatment of Metastatic Melanoma and Solid Tumors
The mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells. Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation. These mutations have become targets for new therapeutic strategies in melanoma and other cancers. Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines. MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma. Trametinib was the first MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib. Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib. The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development. The addition of an anti-PD-1/PD-L1 agent, such as pembrolizumab, durvalumab or atezolizumab, to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma. Binimetinib has also shown efficacy in NRAS-mutated melanoma patients. Future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.
The authors extend special thanks to Alessandra Trocino for providing excellent service and assistance.
Antonio M. Grimaldi and Paolo A. Ascierto prepared the manuscript collaboratively, with input from and approval of all co-authors. All authors read and approved the final manuscript.
Compliance with Ethical Standards
No funding was received for the preparation of this review.
Conflict of interest
Antonio M. Grimaldi has received honoraria from BMS, MSD, Novartis, and Roche Genentech, and had consultant/advisory roles for MSD and Novartis. Ester Simeone has received honoraria from BMS, Novartis, and Roche Genentech, and had a consultant/advisory role for BMS. Paolo A. Ascierto received research founding from BMS, Roche Genentech, and Array Biopharma, and had consulting/advisory roles for BMS, Roche Genentech, MSD, Novartis, Array Biopharma, Amgen, Merck Serono, and Pierre Fabre. Lucia Festino, Vito Vanella, and Martina Strudel declare no conflicts of interest.
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