Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma

Carita, Guillaume; Frisch-Dit-Leitz, Estelle; Dahmani, Ahmed; Raymondie, Chloé; Cassoux, Nathalie; Piperno‐Neumann, Sophie; Némati, Fariba; Laurent, Cécile; Koning, Leanne de; Halilovic, Ensar; Jeay, Sébastien; Wylie, Andrew; Emery, Caroline M.

doi:10.1016/s0959-8049(16)32672-7

Cited by 13 publications

(19 citation statements)

References 27 publications

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“…We focused on increasing our understanding of cellular protein kinase networks, as they represent important (but currently ineffective) druggable modules in metastatic UM downstream of mutated Gα‐subunits of GNAQ/GNA11 . The importance of an unbiased understanding of kinome dynamics to guide therapeutic options is made clear by a recent dissection of responses to targeted kinase therapies in breast cancer models (Bago et al., ) and made relevant to UM by the recent discovery of pathway‐specific kinase inhibitors in human preclinical models (Carita et al., ).…”

Section: Discussionmentioning

confidence: 99%

“…In metastatic UM, progress has been slower still (Carvajal et al., ), with kinase inhibitors showing very limited clinical efficacy, and no clear improvement in overall survival in phase II trials of the multikinase inhibitor sunitinib or the MEK inhibitor selumetinib (Blum, Yang, Komatsubara, & Carvajal, ; Carvajal et al., ). The therapeutic potential of modulating signalling pathways that lie downstream of constitutively active GNAQ/11 , such as AKT, PKC, mTOR and the Hippo‐YAP pathway is currently being evaluated (Carita et al., ; Feng et al., ; Shoushtari & Carvajal, ; Yu et al., ). In addition, targeting cell cycle‐regulated protein kinases remains an attractive approach for therapy in a wide range of solid tumours (Otto & Sicinski, ), although, to our knowledge, this avenue has not been explored experimentally for metastatic UM.…”

Section: Introductionmentioning

confidence: 99%

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Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Bailey

Clarke

Kalirai

et al. 2017

Pigment Cell Melanoma Res

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Bailey

Clarke

Kalirai

et al. 2017

Pigment Cell Melanoma Res

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“…Additionally, AEB071 has shown to inhibit tumor growth in GNAQ mutant xenograft models. As mentioned before, the combination of the PKC inhibitor AEB071 with MEK or mTOR inhibitors has shown a synergistic effect in both in vitro and in vivo studies, suggesting a promising combination for UM therapeutics.…”

Section: Preclinical Approachesmentioning

confidence: 69%

“…The mTOR inhibitor everolimus synergizes with the PI3K inhibitor GDC0941 increasing apoptosis in vitro and blocking tumor growth in patient‐derived xenograft models . Another mTORC1 inhibitor, RAD001, combined with the PKC inhibitor AEB071 has demonstrated a synergistic reduction of tumor growth in patient‐derived xenograft models compared to the single agents alone …”

Section: Preclinical Approachesmentioning

confidence: 99%

Recent advances in uveal melanoma treatment

Álvarez‐Rodríguez

Latorre

Posch

et al. 2017

Medicinal Research Reviews

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Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Recent advances in the understanding of molecular characteristics helped to determine which tumors are most likely to progress. About 50% of patients carrying genetic alterations such as chromosomal aberrations and mutations are at significant risk for metastatic disease of which the majority will succumb to UM within few months. Currently, there is no effective treatment for metastatic uveal melanoma, and we hope this review will encourage researchers and clinicians to work to find a better standard of care.In this article we provide a comprehensive overview of the molecular framework of UM, highlighting the most common mutations involved in this kind of cancer. It also covers the most recent treatments from basic research to clinical trials, including small molecules, nucleic acids or immunotherapy, among others. It is intended to serve as a key reference for clinicians and researchers working in this field.

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“…In melanoma cells, PKC signaling pathway activation was found to be involved in both oncogenic or tumor suppressive effects [34]. Concomitant inhibition of PKC and p53-MDM2 or PKC and mTORC1 pathways efficiently decreased cell survival and increased apoptosis of uveal melanoma cells, providing a very attractive treatment [37]. However, overexpression of the PCKδ isoform in B16F10 melanoma cells resulted in suppressed ceramide production and induced cell death [38].…”

Section: Discussionmentioning

confidence: 99%

Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma

Toricelli

Melo

Hunger

et al. 2017

Cancers

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High TIMP1 expression is associated with poor prognosis in melanoma, where it can bind to CD63 and β1 integrin, inducing PI3-kinase pathway and cell survival. Phosphatidylinositol (3,4,5)-trisphosphate (PIP3), generated under phosphatidylinositol-3-kinase (PI3K) activation, enables the recruitment and activation of protein kinase B (PKB/AKT) and phosphoinositide-dependent kinase 1 (PDK1) at the membrane, resulting in the phosphorylation of a host of other proteins. Using a melanoma progression model, we evaluated the impact of Timp1 and AKT silencing, as well as PI3K, PDK1, and protein kinase C (PKC) inhibitors on aggressiveness characteristics. Timp1 downregulation resulted in decreased anoikis resistance, clonogenicity, dacarbazine resistance, and in vivo tumor growth and lung colonization. In metastatic cells, pAKTThr308 is highly expressed, contributing to anoikis resistance. We showed that PDK1Ser241 and PKCβIISer660 are activated by Timp1 in different stages of melanoma progression, contributing to colony formation and anoikis resistance. Moreover, simultaneous inhibition of Timp1 and AKT in metastatic cells resulted in more effective anoikis inhibition. Our findings demonstrate that Timp1 promotes cell survival with the participation of PDK1 and PKC in melanoma. In addition, Timp1 and AKT act synergistically to confer anoikis resistance in advanced tumor stages. This study brings new insights about the mechanisms by which Timp1 promotes cell survival in melanoma, and points to novel perspectives for therapeutic approaches.

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Dual inhibition of protein kinase C and p53-MDM2 or PKC and mTORC1 are novel efficient therapeutic approaches for uveal melanoma

Cited by 13 publications

References 27 publications

Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Kinome‐wide transcriptional profiling of uveal melanoma reveals new vulnerabilities to targeted therapeutics

Recent advances in uveal melanoma treatment

Timp1 Promotes Cell Survival by Activating the PDK1 Signaling Pathway in Melanoma

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