Atypical KRAS G12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer.

Autor:	Hobbs GA; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Baker NM; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Miermont AM; Thoracic and GI Oncology Branch, NCI, Bethesda, Maryland., Thurman RD; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Pierobon M; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia., Tran TH; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland., Anderson AO; Thoracic and GI Oncology Branch, NCI, Bethesda, Maryland., Waters AM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Diehl JN; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Papke B; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Hodge RG; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Klomp JE; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Goodwin CM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., DeLiberty JM; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Wang J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Ng RWS; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Gautam P; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland., Bryant KL; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Esposito D; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland., Campbell SL; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Petricoin EF 3rd; Center for Applied Proteomics and Molecular Medicine, George Mason University, Manassas, Virginia., Simanshu DK; NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland., Aguirre AJ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.; Broad Institute of MIT and Harvard, Cambridge, Massachusetts., Wolpin BM; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts., Wennerberg K; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.; Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark., Rudloff U; Thoracic and GI Oncology Branch, NCI, Bethesda, Maryland. cjder@med.unc.edu rudloffu@mail.nih.gov.; Rare Tumor Initiative, Pediatric Oncology Branch, NCI, Bethesda, Maryland., Cox AD; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Department of Radiation Oncology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Der CJ; Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina. cjder@med.unc.edu rudloffu@mail.nih.gov.; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.; Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.
Jazyk:	angličtina
Zdroj:	Cancer discovery [Cancer Discov] 2020 Jan; Vol. 10 (1), pp. 104-123. Date of Electronic Publication: 2019 Oct 24.
DOI:	10.1158/2159-8290.CD-19-1006
Abstrakt:	Allele-specific signaling by different KRAS alleles remains poorly understood. The KRAS G12R mutation displays uneven prevalence among cancers that harbor the highest occurrence of KRAS mutations: It is rare (∼1%) in lung and colorectal cancers, yet relatively common (∼20%) in pancreatic ductal adenocarcinoma (PDAC), suggesting context-specific properties. We evaluated whether KRAS G12R is functionally distinct from the more common KRAS G12D - or KRAS G12V -mutant proteins (KRAS G12D/V ). We found that KRAS G12D/V but not KRAS G12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRAS G12D/V - but not KRAS G12R -mutant PDAC. Surprisingly, we found that KRAS G12R is defective for interaction with a key effector, p110α PI3K (PI3Kα), due to structural perturbations in switch II. Instead, upregulated KRAS-independent PI3Kγ activity was able to support macropinocytosis in KRAS G12R -mutant PDAC. Finally, we determined that KRAS G12R -mutant PDAC displayed a distinct drug sensitivity profile compared with KRAS G12D -mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. SIGNIFICANCE: We determined that KRAS G12R is impaired in activating a key effector, p110α PI3K. As such, KRAS G12R is impaired in driving macropinocytosis. However, overexpression of PI3Kγ in PDAC compensates for this deficiency, providing one basis for the prevalence of this otherwise rare KRAS mutant in pancreatic cancer but not other cancers. See related commentary by Falcomatà et al., p. 23 . This article is highlighted in the In This Issue feature, p. 1 . (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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