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

Abstract

Uveal melanoma (UM) is the most common cancer of the eye in adults. Many UM patients develop metastases for which no curative treatment has been identified. Novel therapeutic approaches are therefore urgently needed. UM is characterized by mutations in the genes GNAQ and GNA11 which activate the PKC pathway, leading to the use of PKC inhibitors as a rational strategy to treat UM tumors. Encouraging clinical activity has been noted in UM patients treated with PKC inhibitors. However, it is likely that curative treatment regimens will require a combination of targeted therapeutic agents. Employing a large panel of UM patient-derived xenograft models (PDXs), several PKC inhibitor-based combinations were tested in vivo using the PKC inhibitor AEB071. The most promising approaches were further investigated in vitro using our unique panel of UM cell lines. When combined with AEB071, the two agents CGM097 (p53-MDM2 inhibitor) and RAD001 (mTORC1 inhibitor) demonstrated greater activity than single agents, with tumor regression observed in several UM PDXs. Follow-up studies in UM cell lines on these two drug associations confirmed their combination activity and ability to induce cell death. While no effective treatment currently exists for metastatic uveal melanoma, we have discovered using our unique panel of preclinical models that combinations between PKC/mTOR inhibitors and PKC/p53-MDM2 inhibitors are two novel and very effective therapeutic approaches for this disease. Together, our study reveals that combining PKC and p53-MDM2 or mTORC1 inhibitors may provide significant clinical benefit for UM patients.

• Authors: Guillaume Carita, Estelle Frisch-Dit-Leitz, Ahmed Dahmani, Chloé Raymondie, Nathalie Cassoux, Sophie Piperno-Neumann, Fariba Némati, Cécile Laurent, Leanne De Koning, Ensar Halilovic, Sebastien Jeay, Andrew Wylie, Caroline Emery, Sergio Roman-Roman, Marie Schoumacher, Didier Decaudin
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 23 Pg. 33542-56 (Jun 07 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27507190 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Isoquinolines
• NVP-CGM097
• Piperazines
• Pyrroles
• Quinazolines
• Tumor Suppressor Protein p53
• sotrastaurin
• Everolimus
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Mechanistic Target of Rapamycin Complex 1
• Protein Kinase C

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Everolimus (pharmacology)
• Humans
• Isoquinolines (pharmacology)
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors)
• Melanoma (drug therapy)
• Mice
• Piperazines (pharmacology)
• Protein Kinase C (antagonists & inhibitors)
• Proto-Oncogene Proteins c-mdm2 (antagonists & inhibitors)
• Pyrroles (pharmacology)
• Quinazolines (pharmacology)
• Tumor Suppressor Protein p53 (antagonists & inhibitors)
• Uveal Neoplasms (drug therapy)
• Xenograft Model Antitumor Assays