Journal article
Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer
Proceedings of the National Academy of Sciences - PNAS, Vol.118(51), pp.1-11
12/21/2021
DOI: 10.1073/pnas.2114126118
PMCID: PMC8713765
PMID: 34903667
Abstract
KRAS is mutated in 90% of human pancreatic ductal adenocarcinomas (PDACs). To function, KRAS must localize to the plasma membrane (PM) via a C-terminal membrane anchor that specifically engages phosphatidylserine (PtdSer). This anchor-binding specificity renders KRAS-PM localization and signaling capacity critically dependent on PM PtdSer content. We now show that the PtdSer lipid transport proteins, ORP5 and ORP8, which are essential for maintaining PM PtdSer levels and hence KRAS PM localization, are required for KRAS oncogenesis. Knockdown of either protein, separately or simultaneously, abrogated growth of KRAS-mutant but not KRAS-wild-type pancreatic cancer cell xenografts. ORP5 or ORP8 knockout also abrogated tumor growth in an immune-competent orthotopic pancreatic cancer mouse model. Analysis of human datasets revealed that all components of this PtdSer transport mechanism, including the PM-localized EFR3A-PI4KIII alpha complex that generates phosphatidylinositol-4-phosphate (PI4P), and endoplasmic reticulum (ER)-localized SAC1 phosphatase that hydrolyzes counter transported PI4P, are significantly up-regulated in pancreatic tumors compared to normal tissue. Taken together, these results support targeting PI4KIII alpha in KRAS-mutant cancers to deplete the PM-to-ER PI4P gradient, reducing PM PtdSer content. We therefore repurposed the US Food and Drug Administration-approved hepatitis C antiviral agent, simeprevir, as a PI4KIIIa inhibitor In a PDAC setting. Simeprevir potently mislocalized KRAS from the PM, reduced the clonogenic potential of pancreatic cancer cell lines in vitro, and abrogated the growth of KRAS-dependent tumors in vivo with enhanced efficacy when combined with MAPK and PI3K inhibitors. We conclude that the cellular ER-to-PM PtdSer transport mechanism is essential for KRAS PM localization and oncogenesis and is accessible to therapeutic intervention.
Details
- Title: Subtitle
- Components of the phosphatidylserine endoplasmic reticulum to plasma membrane transport mechanism as targets for KRAS inhibition in pancreatic cancer
- Creators
- Walaa E. Kattan - The University of Texas Health Science Center at HoustonJunchen Liu - The University of Texas Health Science Center at HoustonDina Montufar-Solis - Univ Texas Hlth Sci Ctr Houston, McGovern Med Sch, Dept Integrat Biol & Pharmacol, Houston, TX 77030 USAHong Liang - The University of Texas Health Science Center at HoustonBhargavi Brahmendra Barathi - The University of Texas Health Science Center at HoustonRansome van der Hoeven - The University of Texas Health Science Center at HoustonYong Zhou - The University of Texas Health Science Center at HoustonJohn F. Hancock - The University of Texas Health Science Center at Houston
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.118(51), pp.1-11
- DOI
- 10.1073/pnas.2114126118
- PMID
- 34903667
- PMCID
- PMC8713765
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 0027-8424
- eISSN
- 1091-6490
- Publisher
- Natl Acad Sciences
- Number of pages
- 11
- Grant note
- Dr. John J. Kopchick Fellowship Andrew Sowell-Wade Huggins Fellowship/Professorship in Cancer Research RP200047 / Cancer Prevention and Research Institute of Texas Grant; Cancer Prevention & Research Institute of Texas
- Language
- English
- Date published
- 12/21/2021
- Academic Unit
- Dental Research; Periodontics
- Record Identifier
- 9984737968802771
Metrics
3 Record Views