Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability.

Published online

Journal Article

In human cancers, oncogenic mutations commonly occur in the RAS genes KRAS, NRAS, or HRAS, but there are no clinical RAS inhibitors. Mutations are more prevalent in KRAS, possibly suggesting a unique oncogenic activity mediated by KRAS-specific interaction partners, which might be targeted. Here, we determine the specific protein interactomes of each RAS isoform by BirA proximity-dependent biotin identification. The combined interactomes are screened by CRISPR-Cas9 loss-of-function assays for proteins required for oncogenic KRAS-dependent, NRAS-dependent, or HRAS-dependent proliferation and censored for druggable proteins. Using this strategy, we identify phosphatidylinositol phosphate kinase PIP5K1A as a KRAS-specific interactor and show that PIP5K1A binds to a unique region in KRAS. Furthermore, PIP5K1A depletion specifically reduces oncogenic KRAS signaling and proliferation, and sensitizes pancreatic cancer cell lines to a MAPK inhibitor. These results suggest PIP5K1A as a potential target in KRAS signaling for the treatment of KRAS-mutant cancers.

Full Text

Duke Authors

Cited Authors

  • Adhikari, H; Counter, CM

Published Date

  • September 7, 2018

Published In

Volume / Issue

  • 9 / 1

Start / End Page

  • 3646 -

PubMed ID

  • 30194290

Pubmed Central ID

  • 30194290

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-05692-6

Language

  • eng

Conference Location

  • England