Protein kinase inhibitor responses in uveal melanoma reflects a diminished dependency on PKC-MAPK signaling

John J. Park, Ashleigh Stewart, Mal Irvine, Bernadette Pedersen, Zizhen Ming, Matteo S. Carlino, Russell J. Diefenbach, Helen Rizos*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
19 Downloads (Pure)

Abstract

Uveal melanoma (UM) is a rare cancer arising from melanocytes in the uveal tract of the eye. Despite effective primary treatment, there is no approved therapy for metastatic UM and prognosis and survival remain poor. Over 90% of UM are driven by mutations affecting the Gα subunits encoded by the GNAQ and GNA11 genes. These mutations activate downstream and targetable signaling pathways, including the protein kinase C (PKC) cascade. PKC inhibitors have been used in clinical trials for metastatic UM but have shown limited efficacy. In this study, we examined the signaling and functional effects of two PKC inhibitors (AEB071 and IDE196) in a panel of UM cell models. In response to PKC inhibition, all UM cell lines showed potent suppression of PKC activity, but this was not sufficient to predict PKC inhibitor sensitivity and only two UM cell lines showed substantial PKC inhibitor-induced cell death. The differences in UM cell responses to PKC inhibition were not attributable to the degree or timing of PKC suppression or inhibition of the downstream mitogen-activated protein kinase (MAPK) or phosphatidylinositol-3-kinase (PI3K) pathways. Instead, UM cell show complex, PKC-independent signaling pathways that contribute to their survival and resistance to targeted therapies.

Original languageEnglish
Pages (from-to)1384-1393
Number of pages10
JournalCancer Gene Therapy
Volume29
Issue number10
Early online date29 Mar 2022
DOIs
Publication statusPublished - Oct 2022

Bibliographical note

Copyright the Author(s) 2022. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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