Combined PKC and MEK inhibition in uveal melanoma with GNAQ and GNA11 mutations
11] Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA [2] Departments of Dermatology and Pathology, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.
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 Gαq 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.
Insights
Targeting protein kinase C (PKC) and MEK pathways shows promise for uveal melanoma (UM) with GNAQ/GNA11 mutations. Combined inhibition offers superior efficacy in halting proliferation and inducing apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Uveal melanoma (UM) is a distinct melanoma subtype with limited treatment options for metastatic disease.
- GNAQ and GNA11 mutations are present in 80% of UM cases, driving oncogenic signaling.
- Identifying effector pathways downstream of GNAQ/GNA11 is crucial for targeted therapy development.
Purpose of the Study:
- To investigate the role of protein kinase C (PKC) and MAPK pathways in UM with GNAQ/GNA11 mutations.
- To evaluate the efficacy of PKC and MEK inhibitors, alone and in combination, for UM treatment.
- To identify PKC as a potential therapeutic target in GNAQ/GNA11-mutated UM.
Main Methods:
- Utilized melanoma cell lines with GNAQ or GNA11 mutations.
- Administered PKC inhibitors (AEB071, AHT956) and MEK inhibitors (PD0325901, MEK162).
- Assessed pathway signaling, cell cycle arrest, proliferation, apoptosis, and tumor growth in vitro and in vivo models.
Main Results:
- PKC and MAPK pathways are consistently activated in GNAQ/GNA11-mutated UM.
- PKC inhibition selectively suppressed signaling and induced G1 arrest in GNAQ/GNA11-mutated cells.
- Combined PKC and MEK inhibition demonstrated synergistic effects, halting proliferation and inducing apoptosis in vitro, and causing tumor regression in vivo.
Conclusions:
- PKC is a rational therapeutic target for UM patients with GNAQ or GNA11 mutations.
- Combined MEK and PKC inhibition exhibits superior efficacy compared to monotherapy.
- Combination therapy provides sustained MAP-kinase pathway inhibition and significant anti-tumor activity.
