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The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma.

ABSTRACT: Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently available. The PKC, MAPK and PI3K/AKT/mTOR signaling cascades have been shown to be associated with tumor growth. However, none of the compounds against those pathways results in tumor regression when used as single agents. To identify more effective therapeutic strategies for UM patients, we performed a combination screen using seven targeted agents inhibiting PKC, MEK, AKT, PI3K and mTOR in a panel of ten UM cell lines, representative of the UM disease. We identified a strong synergy between the mTOR inhibitor Everolimus and the PI3K inhibitor GDC0941. This combination resulted in an increase in apoptosis in several UM cell lines compared to monotherapies and enhanced the anti-tumor effect of each single agent in two patient-derived xenografts. Furthermore, we showed that the synergism between the two drugs was associated with the relief by GDC0491 of a reactivation of AKT induced by Everolimus. Altogether, our results highlight a novel and effective combination strategy, which could be beneficial for UM patients.

SUBMITTER: Amirouchene-Angelozzi N

PROVIDER: S-EPMC5029652 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma.

Amirouchene-Angelozzi Nabil N Frisch-Dit-Leitz Estelle E Carita Guillaume G Dahmani Ahmed A Raymondie Chloé C Liot Géraldine G Gentien David D Némati Fariba F Decaudin Didier D Roman-Roman Sergio S Schoumacher Marie M

Oncotarget 20160401 17

Uveal melanoma (UM) is the most frequent malignant ocular tumor in adults. While the primary tumor is efficiently treated by surgery and/or radiotherapy, about one third of UM patients develop metastases, for which no effective treatment is currently available. The PKC, MAPK and PI3K/AKT/mTOR signaling cascades have been shown to be associated with tumor growth. However, none of the compounds against those pathways results in tumor regression when used as single agents. To identify more effectiv ...[more]

PMID: 26988753

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Project description:Background and Aims: Uveal melanoma (UM), the most common primary intraocular tumor in adults, is characterized by marked variability in its ability to metastasize. In fact, up to half the patients with UM develop distant metastases, most commonly to the liver. Mutations in alpha G-protein subunits, GNAQ and GNA11, are found in most primary UM, in a mutually exclusive pattern. Also, mutations in SF3B1, EIF1AX, and BAP1, are associated with markedly distinct prognoses Targeted therapy with MAP kinase inhibitors has been unsuccessful in the treatment of uveal melanoma (UM). The constitutive activation of GNAq and GNA11, typical of MU, determines the activation not only of the MAP kinases but also of the transcription factors YAP / TAZ. It is known that when statins are used to inhibit the HMGCR activity in the mevalonate pathway, the nuclear localization and transcriptional activity of YAP-TAZ are also inhibited mediating a potential anti-cancer activity Methods: We investigated the sensitivity to drugs of a panel of 6 lines of MU, two metastatic and 4 derived from primary tumors, of the latter two were monosomic. We established the IC50s of the individual drugs and the effects of the combinations. The synergistic effects of drugs were studied using MTT proliferation tests, cell cycle and apoptosis. The most synergistic combination was tested in vivo in NSG mice. Results: The synergistic concentrations of trametinib and cerivastatin (T+C) induced a massive arrest of proliferation and cell cycle and an increase of apoptosis 72 hours after the start of treatment particularly in the monosomic, BAP1 mutated UPMM3 cell line. The synergistic effect of T+C was reached after 7 instead of 3 days. In the metastatic OMM2.5 cell line. T+C treatments reduced ERK and AKT phosphorylation and increased the cytoplasmatic, inactive form of YAP. T+C treatment of NSG mice transplanted with the monosomic UM cell line reduced significantly tumor growth. Conclusion: This study suggests that statins potentiate the efficacy of MEK inhibitors in the therapy of UM

Project description:BackgroundThe critical role of phosphoinositide 3-kinase (PI3K) activation in tumor cell biology has prompted massive efforts to develop PI3K inhibitors (PI3Kis) for cancer therapy. However, recent results from clinical trials have shown only a modest therapeutic efficacy of single-agent PI3Kis in solid tumors. Targeting autophagy has controversial context-dependent effects in cancer treatment. As a FDA-approved lysosomotropic agent, hydroxychloroquine (HCQ) has been well tested as an autophagy inhibitor in preclinical models. Here, we elucidated the novel mechanism of HCQ alone or in combination with PI3Ki BKM120 in the treatment of cancer.MethodsThe antitumor effects of HCQ and BKM120 on three different types of tumor cells were assessed by in vitro PrestoBlue assay, colony formation assay and in vivo zebrafish and nude mouse xenograft models. The involved molecular mechanisms were investigated by MDC staining, LC3 puncta formation assay, immunofluorescent assay, flow cytometric analysis of apoptosis and ROS, qRT-PCR, Western blot, comet assay, homologous recombination (HR) assay and immunohistochemical staining.ResultsHCQ significantly sensitized cancer cells to BKM120 in vitro and in vivo. Interestingly, the sensitization mediated by HCQ could not be phenocopied by treatment with other autophagy inhibitors (Spautin-1, 3-MA and bafilomycin A1) or knockdown of the essential autophagy genes Atg5/Atg7, suggesting that the sensitizing effect might be mediated independent of autophagy status. Mechanistically, HCQ induced ROS production and activated the transcription factor NRF2. In contrast, BKM120 prevented the elimination of ROS by inactivation of NRF2, leading to accumulation of DNA damage. In addition, HCQ activated ATM to enhance HR repair, a high-fidelity repair for DNA double-strand breaks (DSBs) in cells, while BKM120 inhibited HR repair by blocking the phosphorylation of ATM and the expression of BRCA1/2 and Rad51.ConclusionsOur study revealed that HCQ and BKM120 synergistically increased DSBs in tumor cells and therefore augmented apoptosis, resulting in enhanced antitumor efficacy. Our findings provide a new insight into how HCQ exhibits antitumor efficacy and synergizes with PI3Ki BKM120, and warn that one should consider the "off target" effects of HCQ when used as autophagy inhibitor in the clinical treatment of cancer.

Dataset Information

The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma.

Publications

The mTOR inhibitor Everolimus synergizes with the PI3K inhibitor GDC0941 to enhance anti-tumor efficacy in uveal melanoma.

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