دورية أكاديمية
PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma
| العنوان: | PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma |
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| المؤلفون: | Park, John J., Hamad, Sabine Abou, Stewart, Ashleigh, Carlino, Matteo S., Lim, Su Yin, Rizos, Helen |
| المصدر: | Park , J J , Hamad , S A , Stewart , A , Carlino , M S , Lim , S Y & Rizos , H 2024 , ' PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma ' , Oncogenesis , vol. 13 , no. 1 , 9 , pp. 1-9 . https://doi.org/10.1038/s41389-024-00511-8Test |
| سنة النشر: | 2024 |
| الوصف: | Protein kinase C (PKC) is activated downstream of gain-of-function GNAQ or GNA11 (GNAQ/GNA11) mutations in over 90% of uveal melanoma (UM). Phase I clinical trials of PKC inhibitors have shown modest response rates with no survival benefit in metastatic UM. Although PKC inhibitors actively suppress mitogen-activated protein kinase (MAPK) signalling in UM, the effect on other UM signalling cascades is not well understood. We examined the transcriptome of UM biopsies collected pre- and post-PKC inhibitor therapy and confirmed that MAPK, but not PI3K/AKT signalling, was inhibited early during treatment with the second-generation PKC inhibitor IDE196. Similarly, in GNAQ/GNA11-mutant UM cell models, PKC inhibitor monotherapy effectively suppressed MAPK activity, but PI3K/AKT signalling remained active, and thus, concurrent inhibition of PKC and PI3K/AKT signalling was required to synergistically induce cell death in a panel of GNAQ/GNA11-mutant UM cell lines. We also show that re-activation of MAPK signalling has a dominant role in regulating PKC inhibitor responses in UM and that PI3K/AKT signalling diminishes UM cell sensitivity to PKC inhibitor monotherapy. Thus, combination therapies targeting PKC and PKC-independent signalling nodes, including PI3K/AKT activity, are required to improve responses in patients with metastatic UM. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| DOI: | 10.1038/s41389-024-00511-8 |
| الإتاحة: | https://doi.org/10.1038/s41389-024-00511-8Test https://researchers.mq.edu.au/en/publications/44bab00d-4654-47ff-ade4-c37e2e58233cTest https://research-management.mq.edu.au/ws/files/327653050/Publisher_version_open_access_.pdfTest http://www.scopus.com/inward/record.url?scp=85186251815&partnerID=8YFLogxKTest |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.6E43E5BF |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41389-024-00511-8 |
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