Abstract 2703
Background
Uveal melanoma (UM) is a rare cancer that arises from melanocytes in the uveal tract of the eye. Despite effective treatment for primary UM, > 50% of patients develop metastatic disease. There is currently no effective treatment for metastatic UM and median life expectancy is < 8 months. About 90% of UM are characterised by mutations in the GNAQ or GNA11 GTPases and several signalling cascades downstream of G-protein activation have been identified as potentially targetable. These include the protein kinase C (PKC), mitogen activated protein kinase (MAPK), phosphatidylinositol-3-kinases (PI3K), mammalian target of rapamycin (mTOR), and YES-associated protein (YAP) pathways. Aim to understand the relative contribution of oncogenic signaling pathways in proliferation and survival of UM.
Methods
The response 11 UM cell lines to 6 selective inhibitors was investigated using cell viability assays and cell cycle analyses by flow cytometry. Inhibition of selected pathways was examined using Western analysis of downstream effector proteins. The inhibitors used in this study included PKC inhibitors (AEB071 and LXS196), MEK inhibitor (trametinib), PI3K/mTOR inhibitor (BEZ235), YAP inhibitor (verteporfin) and ARF6 inhibitor (NAV2729).
Results
PKC inhibitors were most effective with 8 GNAQ/11 mutant UM cell lines showing some degree of sensitivity to each of the inhibitors, although sensitivity was usually associated with proliferative arrest rather than cell death. (see Table) Expression levels of pMARCKS and pERK were strongly inhibited by PKC inhibitors, however inhibition of these effector proteins did not reflect the degree of UM cell sensitivity.Table:
21P Summary of UM cell lines to each inhibitor. Combined result of cell viability assay and cell cycle analysis
Cell Line | Mutation | Trametinib | BEZ235 | NAV2729 | AEB071 | Verteporfin | LXS196 |
---|---|---|---|---|---|---|---|
Mel270 | GNAQ | sensitive | sensitive | sensitive | sensitive | sensitive | sensitive |
OMM1 | GNA11 | resistant | sensitive | intermediate sensitivity | sensitive | sensitive | sensitive |
92.1 | GNAQ | resistant | intermediate sensitivity | sensitive | intermediate sensitivity | sensitive | intermediate sensitivity |
Mel202 | GNAQ | resistant | intermediate sensitivity | sensitive | intermediate sensitivity | sensitive | intermediate sensitivity |
OMM1.3 | GNAQ | resistant | intermediate sensitivity | resistant | intermediate sensitivity | resistant | intermediate sensitivity |
OMM1.5 | GNAQ | resistant | resistant | resistant | intermediate sensitivity | resistant | intermediate sensitivity |
MP41 | GNA11 | resistant | resistant | resistant | intermediate sensitivity | resistant | intermediate sensitivity |
MP46 | GNAQ | resistant | resistant | resistant | resistant | resistant | intermediate sensitivity |
MP38 | GNAQ | resistant | resistant | resistant | resistant | resistant | resistant |
Mel290 | Nil | resistant | intermediate sensitivity | resistant | resistant | resistant | resistant |
Mel285 | Nil | resistant | resistant | resistant | resistant | resistant | resistant |
Conclusions
The sensitivity of GNAQ/11 mutation UM cell lines to 6 targeted drugs is heterogeneous and no single dominant signalling pathway was identified. This suggest that multiple, independent signal pathways contribute to the survival of UM. Thus, inhibition of any single pathway is unlikely to be effective in the treatment of majority of metastatic UM.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
Resources from the same session
4526 - Long-term outcome of neoadjuvant tyrosine kinase inhibitors (TKI) in locally advanced dermatofibrosarcoma protuberans (DFSP)
Presenter: Jessica Beaziz
Session: Poster Display session 1
Resources:
Abstract
1214 - Neo-adjuvant (NA) Imatinib for gastrointestinal stromal tumours (GISTs): What is the optimal length of treatment?
Presenter: Tom Wilson
Session: Poster Display session 1
Resources:
Abstract
2690 - Gastrointestinal Stromal Tumours (GIST) in adolescents and young adults (AYA)
Presenter: Nikki Ijzerman
Session: Poster Display session 1
Resources:
Abstract
4558 - Radiomics improves response evaluation for desmoid tumors treated with chemotherapy
Presenter: Amandine Crombe
Session: Poster Display session 1
Resources:
Abstract
2751 - Radiomics of gastrointestinal stromal tumors; risk classification based on computed tomography images – a pilot study
Presenter: Milea Timbergen
Session: Poster Display session 1
Resources:
Abstract
2737 - Differentiating well-differentiated liposarcomas from lipomas using a radiomics approach
Presenter: Melissa Vos
Session: Poster Display session 1
Resources:
Abstract
1282 - The immune landscape of chondrosarcoma reveals an anti inflammatory environment
Presenter: Iseulys Richert
Session: Poster Display session 1
Resources:
Abstract
1572 - Impact of Immunotherapy and Targeted Therapy on Tumor Growth Rate in Sarcoma
Presenter: Esmail Al-ezzi
Session: Poster Display session 1
Resources:
Abstract
3414 - DNA methylation profiles of angiosarcoma subtypes.
Presenter: Marije Weidema
Session: Poster Display session 1
Resources:
Abstract
3411 - Prognostic significance of circulating PD-1, PD-L1, pan-BTN3As and BTN3A1 in patients with metastatic gastrointestinal stromal tumors (mGISTs)
Presenter: Daniele Fanale
Session: Poster Display session 1
Resources:
Abstract