不依赖 PKC 的 PI3K 信号降低了葡萄膜黑色素瘤对 PKC 抑制剂的敏感性

IF 5.9 2区 医学 Q1 ONCOLOGY Oncogenesis Pub Date : 2024-02-28 DOI:10.1038/s41389-024-00511-8
John J. Park, Sabine Abou Hamad, Ashleigh Stewart, Matteo S. Carlino, Su Yin Lim, Helen Rizos
{"title":"不依赖 PKC 的 PI3K 信号降低了葡萄膜黑色素瘤对 PKC 抑制剂的敏感性","authors":"John J. Park, Sabine Abou Hamad, Ashleigh Stewart, Matteo S. Carlino, Su Yin Lim, Helen Rizos","doi":"10.1038/s41389-024-00511-8","DOIUrl":null,"url":null,"abstract":"<p>Protein kinase C (PKC) is activated downstream of gain-of-function <i>GNAQ</i> or <i>GNA11</i> (<i>GNAQ/GNA11</i>) 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.</p><figure></figure>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"82 1","pages":""},"PeriodicalIF":5.9000,"publicationDate":"2024-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma\",\"authors\":\"John J. Park, Sabine Abou Hamad, Ashleigh Stewart, Matteo S. Carlino, Su Yin Lim, Helen Rizos\",\"doi\":\"10.1038/s41389-024-00511-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Protein kinase C (PKC) is activated downstream of gain-of-function <i>GNAQ</i> or <i>GNA11</i> (<i>GNAQ/GNA11</i>) 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.</p><figure></figure>\",\"PeriodicalId\":19489,\"journal\":{\"name\":\"Oncogenesis\",\"volume\":\"82 1\",\"pages\":\"\"},\"PeriodicalIF\":5.9000,\"publicationDate\":\"2024-02-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Oncogenesis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41389-024-00511-8\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ONCOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Oncogenesis","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41389-024-00511-8","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

在超过90%的葡萄膜黑色素瘤(UM)中,蛋白激酶C(PKC)在功能增益型GNAQ或GNA11(GNAQ/GNA11)突变的下游被激活。PKC 抑制剂的 I 期临床试验显示,转移性 UM 的反应率不高,但无生存获益。虽然PKC抑制剂能积极抑制UM中的丝裂原活化蛋白激酶(MAPK)信号传导,但对UM其他信号级联的影响尚不十分清楚。我们研究了在 PKC 抑制剂治疗前后收集的 UM 活检组织的转录组,结果证实,在使用第二代 PKC 抑制剂 IDE196 治疗的早期,MAPK(而非 PI3K/AKT 信号)受到抑制。同样,在 GNAQ/GNA11 突变 UM 细胞模型中,PKC 抑制剂单药治疗能有效抑制 MAPK 活性,但 PI3K/AKT 信号仍处于活跃状态,因此,在一组 GNAQ/GNA11 突变 UM 细胞系中,需要同时抑制 PKC 和 PI3K/AKT 信号才能协同诱导细胞死亡。我们还发现,MAPK 信号的重新激活在调节 UM 对 PKC 抑制剂的反应中起着主导作用,而 PI3K/AKT 信号会降低 UM 细胞对 PKC 抑制剂单一疗法的敏感性。因此,需要针对 PKC 和 PKC 依赖性信号节点(包括 PI3K/AKT 活性)的联合疗法来改善转移性 UM 患者的反应。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

摘要图片

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
PKC-independent PI3K signalling diminishes PKC inhibitor sensitivity in uveal melanoma

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.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Oncogenesis
Oncogenesis ONCOLOGY-
CiteScore
11.90
自引率
0.00%
发文量
70
审稿时长
26 weeks
期刊介绍: Oncogenesis is a peer-reviewed open access online journal that publishes full-length papers, reviews, and short communications exploring the molecular basis of cancer and related phenomena. It seeks to promote diverse and integrated areas of molecular biology, cell biology, oncology, and genetics.
期刊最新文献
Tumor cell-derived ISG15 promotes fibroblast recruitment in oral squamous cell carcinoma via CD11a-dependent glycolytic reprogramming. CENPF (+) cancer cells promote malignant progression of early-stage TP53 mutant lung adenocarcinoma. STAG2 expression imparts distinct therapeutic vulnerabilities in muscle-invasive bladder cancer cells. Proteomic meta-analysis unveils new frontiers for biomarkers research in pancreatic carcinoma. Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1