Abstract 2345: Combined inhibition of protein kinase C and MEK is a rational therapeutic approach for melanomas with GNAQ or GNA11 mutations.

Abstract

Abstract Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults. There currently is no effective treatment for metastatic UM. UM differs from cutaneous melanoma in that it lacks BRAF, NRAS, or KIT mutations but instead harbors mutations in the Gαq family members GNAQ and GNA11 in over 80 to 90% of cases. Understanding the downstream effector pathways of these oncoproteins is of considerable interest to identify opportunities for targeted therapy. Using 293T cells, immortalized mouse and human melanocytes, we find that GNAQQ209L or GNA11Q209L induce activation of the protein kinase C (PKC) and MAPK pathways. ShRNA mediated knock-down of mutant GNAQ abrogates both PKC and MAPK activation in human melanoma cell lines or model systems. Using two different PKC inhibitors we found selective extinction of PKC and MAPK signalling and induction of G1 arrest in panels of melanoma cell lines carrying GNAQ or GNA11 mutations, whereas no such effect was observed in melanoma cell lines with other mutations. MAPK activation occurred downstream of activated PKC in cells with GNAQ or GNA11 mutations. In contrast to PKC inhibitors, which selectively inhibited the growth of melanoma cell lines with GNAQ or GNA11 mutations, the MEK inhibitor PD0325901 inhibited melanoma cell lines irrespective of their GNAQ/11 mutation status. In vivo the PKC inhibitor AEB071 slowed the growth of tumors in an allograft model of GNAQQ209L transduced melanocytes, but did not induce tumor shrinkage. Analysis of tumor lysates identified suppression of PKC signaling but not of MAP-kinase pathway signaling under chronic PKC inhibition. The rebound of MAP-kinase activation could be overcome using a combination of AEB071 with the MEK inhibitor PD0325901, which showed strong synergy in halting proliferation and in inducing apoptosis. Our data suggest that PKC is a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and indicate that a combination therapy with MEK inhibitor is superior to treatment with either approach alone. Citation Format: Xu Chen, Qiuxia Wu, Boris C. Bastian. Combined inhibition of protein kinase C and MEK is a rational therapeutic approach for melanomas with GNAQ or GNA11 mutations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2345. doi:10.1158/1538-7445.AM2013-2345