Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations Journal Article

Authors: Chen, X.; Wu, Q.; Tan, L.; Porter, D.; Jager, M. J.; Emery, C.; Bastian, B. C.
Article Title: Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations
Abstract: Uveal melanoma (UM) is a genetically and biologically distinct type of melanoma, and once metastatic there is no effective treatment currently available. Eighty percent of UMs harbor mutations in the G alpha(q) family members GNAQ and GNA11. Understanding the effector pathways downstream of these oncoproteins is important to identify opportunities for targeted therapy. We report consistent activation of the protein kinase C (PKC) and MAPK pathways as a consequence of GNAQ or GNA11 mutation. PKC inhibition with AEB071 or AHT956 suppressed PKC and MAPK signalling and induced G1 arrest selectively in melanoma cell lines carrying GNAQ or GNA11 mutations. In contrast, treatment with two different MEK inhibitors, PD0325901 and MEK162, inhibited the proliferation of melanoma cell lines irrespective of their mutation status, indicating that in the context of GNAQ or GNA11 mutation MAPK activation can be attributed to activated PKC. AEB071 significantly slowed the growth of tumors in an allograft model of GNAQ(Q209L)-transduced melanocytes, but did not induce tumor shrinkage. In vivo and in vitro studies showed that PKC inhibitors alone were unable to induce sustained suppression of MAP-kinase signaling. However, combinations of PKC and MEK inhibition, using either PD0325901or MEK162, led to sustained MAP-kinase pathway inhibition and showed a strong synergistic effect in halting proliferation and in inducing apoptosis in vitro. Furthermore, combining PKC and MEK inhibition was efficacious in vivo, causing marked tumor regression in a UM xenograft model. Our data identify PKC as a rational therapeutic target for melanoma patients with GNAQ or GNA11 mutations and demonstrate that combined MEK and PKC inhibition is synergistic, with superior efficacy compared to treatment with either approach alone.
Keywords: melanoma; protein kinase c; resistance; lung-cancer; phase-ii; inhibition; protein-kinase-c; pathway; raf; signal-regulated kinase; alpha-subunit; mapk signaling; braf inhibition; gnaq/gna11; combined pkc and mek; pkc inhibitor; promoting phorbol esters
Journal Title: Oncogene
Volume: 33
Issue: 39
ISSN: 0950-9232
Publisher: Nature Publishing Group  
Date Published: 2014-09-25
Start Page: 4724
End Page: 4734
Language: English
ACCESSION: WOS:000343239500003
DOI: 10.1038/onc.2013.418
PUBMED: 24141786
PMCID: PMC4524511
Notes: Article -- Source: Wos
Citation Impact
MSK Authors
  1. Boris Christoph Bastian
    18 Bastian
  2. Xu Chen
    6 Chen