Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies
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LEADING ARTICLE
Mechanisms of Resistance to BRAF‑Targeted Melanoma Therapies Ozgecan Dulgar1 · Tugce Kutuk1 · Zeynep Eroglu1,2
© Springer Nature Switzerland AG 2020
Abstract About half of all cutaneous melanomas harbor activating mutations in the BRAF oncogene. Dependence on this pathway makes the tumors vulnerable to BRAF (and downstream MEK) inhibition, and three drug combinations are approved to target this vulnerability in advanced melanomas with BRAFV600 mutations. Responses to BRAF/MEK inhibitors are usually fast, but durability of response can be limited. Five-year data from BRAF/MEK inhibitors show long-term survival benefit for a third of the patients. There is a wide variety of known mechanisms of resistance to BRAF/MEK inhibition, such as mitogen-activated protein kinase reactivation, activation of parallel pathways, alterations in cell-cycle regulation, and nongenetic resistance mechanisms. Strategies that have been explored to overcome these mechanisms include alternative dosing regimens, addition of another kinase inhibitor, and use of anti-PD-1 immunotherapy either in combination or post-relapse on BRAF/MEK inhibitor therapies.
1 Introduction Melanoma is the leading cause of death from cutaneous malignancies. It is the most common cancer in adults aged 25–29 years, although the median age at diagnosis is 59 years [1]. Approximately 40–50% of cutaneous melanomas harbor mutations in the BRAF oncogene, which is the most frequently targeted somatic mutation in melanoma [2]. Activating mutations in codon 600 of BRAF, including V600E (80%), V600K (15%), and V600R/M/D/G (5%), are more common in younger patients at diagnosis, and melanomas on skin with intermittent sun-induced damage [3, 4]. The mitogen-activated protein kinase (MAPK) pathway, which includes the RAS, RAF, MEK, and ERK proteins, is activated in nearly all melanomas [5, 6]. In healthy cells, the tightly regulated MAPK pathway transmits extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events through RAS GTPases and the serine/threonine kinases of RAF, MEK, and ERK [7]. BRAFV600 mutant proteins in melanoma constitutively activate the MAPK pathway, and this
* Zeynep Eroglu [email protected] 1
Department of Cutaneous Oncology, Moffitt Cancer Center, Tampa, FL, USA
Department of Oncologic Sciences, University of South Florida/Morsani School of Medicine, Tampa, FL, USA
2
Key Points There are various strategies under exploration to overcome resistance to BRAF-targeted therapies. However, given the significant diversity of mechanisms of resistance to BRAF/MEK inhibitors, targeting specific mechanisms to improve treatment benefit in patients has remained challenging. The addition of a third kinase inhibitor to BRAF/MEK inhibitors to target a specific resistance mechanism may lead to worsening drug toxicity, and thus these regimens may not be tolerable at drug concentrations needed to maintain mitogen-activated protein kinase pathway inhibition While re-challenge with BRAF/MEK inhibitor
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