Format

Send to

Choose Destination
Nat Commun. 2018 Sep 7;9(1):3646. doi: 10.1038/s41467-018-05692-6.

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

Author information

1
Department of Pharmacology and Cancer Biology, Duke University Medical Center, DUMC-3813, Durham, NC, 27713, USA.
2
Department of Pharmacology and Cancer Biology, Duke University Medical Center, DUMC-3813, Durham, NC, 27713, USA. count004@mc.duke.edu.
3
Department of Radiation Oncology, Duke University Medical Center, DUMC-3813, Durham, NC, 27713, USA. count004@mc.duke.edu.

Abstract

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.

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center