Abstract
The RAS/BRAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway is emerging as a key modulator of melanoma initiation and progression. However, a variety of clinical studies indicate that inhibiting the MAPK pathway is insufficient per se to effectively kill melanoma cells. Here, we report on a genetic and pharmacologic approach to identify survival factors responsible for the resistance of melanoma cells to MEK/ERK antagonists. In addition, we describe a new tumor cell-selective means to bypass this resistance in vitro and in vivo. By generating a panel of isogenic cell lines with specific defects in the apoptotic machinery, we found that the ability of melanoma cells to survive in the absence of functional MEK relies on an ERK-independent expression of the antiapoptotic factor Mcl-1 (and to a lesser extent, Bcl-x(L) and Bcl-2). Using computer-based modeling, we developed a novel Bcl-2 homology domain 3 (BH3) mimetic. This compound, named TW-37, is the first rationally designed small molecule with high affinity for Mcl-1, Bcl-x(L), and Bcl-2. Mechanistic analyses of the mode of action of TW-37 showed a synergistic tumor cell killing in the presence of MEK inhibitors. Importantly, TW-37 unveiled an unexpected role of the MAPK pathway in the control of reactive oxygen species (ROS). This function was critical to prevent the activation of proapoptotic functions of p53 in melanoma cells, but surprisingly, it was dispensable for normal melanocytes. Our results suggest that this MAPK-dependent ROS/p53 feedback loop is a point of vulnerability of melanoma cells that can be exploited for rational drug design.
Highlights
The identification of tumor-associated genetic and epigenetic hallmarks is providing a rational platform for molecularly targeted cancer therapies [1, 2]
It has been recently reported that NRASand BRAF-expressing melanoma cells have a different sensitivity to inhibitors of the mitogen-activated protein kinase (MAPK) pathway [25]
We describe an unexpected interplay between the MAPK pathway and antiapoptotic factors in the control of melanoma cell viability
Summary
The identification of tumor-associated genetic and epigenetic hallmarks is providing a rational platform for molecularly targeted cancer therapies [1, 2]. The apoptotic machinery, the intrinsic or mitochondrial pathway, is defective in aggressive melanoma cells [6, 8]. Inhibition of caspases can result from the increased expression of several members of the inhibitors of apoptosis proteins (IAP) family [12] and/or by downregulation of APAF-1, a cofactor of caspase-9 [13, 14]. Overexpression of proteins such as SURVIVIN, which act at the interface between cell cycle progression and death, can contribute to the aggressive phenotype of melanoma cells [8]
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