Cargando…
Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity
The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS inte...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429657/ https://www.ncbi.nlm.nih.gov/pubmed/34504076 http://dx.doi.org/10.1038/s41467-021-25523-5 |
_version_ | 1783750575038398464 |
---|---|
author | Adhikari, Hema Kattan, Walaa E. Kumar, Shivesh Zhou, Pei Hancock, John F. Counter, Christopher M. |
author_facet | Adhikari, Hema Kattan, Walaa E. Kumar, Shivesh Zhou, Pei Hancock, John F. Counter, Christopher M. |
author_sort | Adhikari, Hema |
collection | PubMed |
description | The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRAS(G12C) inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers. |
format | Online Article Text |
id | pubmed-8429657 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84296572021-09-24 Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity Adhikari, Hema Kattan, Walaa E. Kumar, Shivesh Zhou, Pei Hancock, John F. Counter, Christopher M. Nat Commun Article The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate how RAS oncoproteins signal, we mined RAS interactomes for potential vulnerabilities. Here we identify EFR3A, an adapter protein for the phosphatidylinositol kinase PI4KA, to preferentially bind oncogenic KRAS. Disrupting EFR3A or PI4KA reduces phosphatidylinositol-4-phosphate, phosphatidylserine, and KRAS levels at the plasma membrane, as well as oncogenic signaling and tumorigenesis, phenotypes rescued by tethering PI4KA to the plasma membrane. Finally, we show that a selective PI4KA inhibitor augments the antineoplastic activity of the KRAS(G12C) inhibitor sotorasib, suggesting a clinical path to exploit this pathway. In sum, we have discovered a distinct KRAS signaling axis with actionable therapeutic potential for the treatment of KRAS-mutant cancers. Nature Publishing Group UK 2021-09-09 /pmc/articles/PMC8429657/ /pubmed/34504076 http://dx.doi.org/10.1038/s41467-021-25523-5 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Adhikari, Hema Kattan, Walaa E. Kumar, Shivesh Zhou, Pei Hancock, John F. Counter, Christopher M. Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity |
title | Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity |
title_full | Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity |
title_fullStr | Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity |
title_full_unstemmed | Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity |
title_short | Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity |
title_sort | oncogenic kras is dependent upon an efr3a-pi4ka signaling axis for potent tumorigenic activity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429657/ https://www.ncbi.nlm.nih.gov/pubmed/34504076 http://dx.doi.org/10.1038/s41467-021-25523-5 |
work_keys_str_mv | AT adhikarihema oncogenickrasisdependentuponanefr3api4kasignalingaxisforpotenttumorigenicactivity AT kattanwalaae oncogenickrasisdependentuponanefr3api4kasignalingaxisforpotenttumorigenicactivity AT kumarshivesh oncogenickrasisdependentuponanefr3api4kasignalingaxisforpotenttumorigenicactivity AT zhoupei oncogenickrasisdependentuponanefr3api4kasignalingaxisforpotenttumorigenicactivity AT hancockjohnf oncogenickrasisdependentuponanefr3api4kasignalingaxisforpotenttumorigenicactivity AT counterchristopherm oncogenickrasisdependentuponanefr3api4kasignalingaxisforpotenttumorigenicactivity |