TY - JOUR
T1 - Interrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability
AU - Adhikari, Hema
AU - Counter, Christopher M.
N1 - Funding Information:
This work is supported by NIH grants R01CA123031 and P01CA203657 (C.M.C.) and by a Pancreatic Cancer Action Network-NCI Fredrick National Laboratory for Cancer Research KRAS Fellowship (H.A.). We thank the Duke Cancer Institute Proteomics Facility for performing the mass spectrometry analysis, the Fred Hutchinson Cancer Center Sequencing Facility for sequence analysis, and Kris Wood and Sarah Goetz (DUMC) for technical advice.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052998144&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05692-6
DO - 10.1038/s41467-018-05692-6
M3 - Article
C2 - 30194290
AN - SCOPUS:85052998144
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3646
ER -