Abstract
Improving treatment of advanced melanoma may require the development of effective strategies to overcome resistance to different anti-tumor agents and to counteract relevant pro-tumoral mechanisms in the microenvironment. Here we provide preclinical evidence that these goals can be achieved in most melanomas, by co-targeting of oncogenic and death receptor pathways, and independently of their BRAF, NRAS, p53 and PTEN status. In 49 melanoma cell lines, we found independent susceptibility profiles for response to the MEK1/2 inhibitor AZD6244, the PI3K/mTOR inhibitor BEZ235 and the death receptor ligand TRAIL, supporting the rationale for their association. Drug interaction analysis indicated that a strong synergistic anti-tumor activity could be achieved by the three agents and the AZD6244–TRAIL association on 20/21 melanomas, including cell lines resistant to the inhibitors or to TRAIL. Mechanistically, synergy was explained by enhanced induction of caspase-dependent apoptosis, mitochondrial depolarization and modulation of key regulators of extrinsic and intrinsic cell death pathways, including c-FLIP, BIM, BAX, clusterin, Mcl-1 and several IAP family members. Moreover, silencing experiments confirmed the central role of Apollon downmodulation in promoting the apoptotic response of melanoma cells to the combinatorial treatments. In SCID mice, the AZD6244–TRAIL association induced significant growth inhibition of a tumor resistant to TRAIL and poorly responsive to AZD6244, with no detectable adverse events on body weight and tissue histology. Reduction in tumor volume was associated not only with promotion of tumor apoptosis but also with suppression of the pro-angiogenic molecules HIF1α, VEGFα, IL-8 and TGFβ1 and with inhibition of tumor angiogenesis. These results suggest that synergistic co-targeting of oncogenic and death receptor pathways can not only overcome melanoma resistance to different anti-tumor agents in vitro but can also promote pro-apoptotic effects and inhibition of tumor angiogenesis in vivo.
Highlights
The latter approach is based on the combination of specific inhibitors of main oncogenic pathways, which in different
Cell Death and Disease whether concomitant resistance to mitogen/extracellular signalregulated kinase (MEK), phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors and to the death receptor ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is frequent in human melanoma
We found that response to TRAIL correlated significantly with caspase-8 cleavage (P = 0.0086) but even with mitochondrial depolarization (Po0.0001, Figure 1b and Supplementary Table S1), in agreement with the notion that melanoma cells behave as type II cells in response to TRAIL, requiring activation of the intrinsic pathway of cell death.[24]
Summary
The latter approach is based on the combination of specific inhibitors of main oncogenic pathways, which in different. The interest in the death receptor pathway, as a therapeutic target, has been recently strengthened by the evidence that TRAIL mediates disruption of the tumor-associated vasculature[21] and by the discovery of TIC10, a drug that stimulates production of TRAIL and that exerts significant anti-tumor activities in preclinical in vivo models, including aggressive intracranial xenografts of human glioblastoma cells.[22] It is currently not known whether co-targeting of MEK and/or PI3K/mammalian target of rapamycin (mTOR) and of the death receptor pathway in melanoma can overcome intrinsic resistance to each of the anti-tumor agents in most instances, irrespective of the different genetic make-up of the tumors, and whether this approach can exert synergistic, rather than additive, anti-melanoma effects. An in vivo model showed that the AZD6244/TRAIL association promoted melanoma apoptosis associated with marked inhibition of angiogenesis
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