Atypical KRASG12R Mutant Is Impaired in PI3K Signaling and Macropinocytosis in Pancreatic Cancer
Open accessPublished version of a preprint
Abstract
Allele-specific signaling by different KRAS alleles remains poorly understood. The KRASG12R 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 KRASG12R is functionally distinct from the more common KRASG12D- or KRASG12V-mutant proteins (KRASG12D/V). We found that KRASG12D/V but not KRASG12R drives macropinocytosis and that MYC is essential for macropinocytosis in KRASG12D/V- but not KRASG12R-mutant PDAC. Surprisingly, we found that KRASG12R 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 KRASG12R-mutant PDAC. Finally, we determined that KRASG12R-mutant PDAC displayed a distinct drug sensitivity profile compared with KRASG12D-mutant PDAC but is still responsive to the combined inhibition of ERK and autophagy. Significance: We determined that KRASG12R is impaired in activating a key effector, p110α PI3K. As such, KRASG12R 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
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Pancreatic cancer has a higher prevalence of G12R compared to lung adenocarcinoma and colorectal cancer, consistent with MAPK being the dominant signaling pathway driving pancreatic cancer.
“Compared to other KRAS-driven diseases like lung adenocarcinoma and colorectal cancer, pancreatic cancer has a higher prevalence of G12R, consistent with MAPK being the dominant signaling pathway driving pancreatic cancer [36,37].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [36]
The Introduction (page not provided) says KRAS G12R is rare in lung and colorectal cancers (~1%) but is the third most common KRAS mutation in pancreatic ductal adenocarcinoma. The Results and Discussion examine MAPK inhibition in pancreatic cancer, but do not establish that MAPK is the dominant pathway driving pancreatic cancer; that part of the attributed claim is unsupported. (LLM, conf=0.85)
Experimental — accuracy not yet measuredKRAS G12R exhibits a reduced affinity for PI3K binding in pancreatic ductal adenocarcinoma relative to other KRAS G12D and G12V mutants, leading to impaired PI3K signaling.
“Notably, KRAS G12R exhibits a reduced affinity for PI3K binding in PDAC relative to other KRAS G12D and G12V mutants, leading to impaired PI3K signaling [36].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [36]
Additional biochemical, structural, and signaling distinctions have been identified between different mutant KRAS alleles, including between those at the same amino acid position.
“Additional biochemical, structural, and signaling distinctions have been identified between different mutant alleles, including between those at the same amino acid position4,8,13–20.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [14]
KRASG12R has an altered switch-II structure that cannot activate p110α/PI3K directly.
“It has distinct biochemical features from KRASG12D/V including an altered switch-II structure that cannot activate p110α/PI3K directly43.”
From Impact of KRAS mutations and co-mutations on clinical outcomes in pancreatic ductal adenocarcinoma (2024) · cites this paper as [43]
A146T and Q61H KRAS mutations remain sensitive to pan-KRAS inhibitors and degraders targeting the OFF form of KRAS, whereas KRAS G12R may require KRAS ON drugs.
“While A146T and Q61H mutations in KRAS remain sensitive to pan-KRAS inhibitors and degraders targeting the “OFF” form of KRAS, this appears not the case for the KRAS G12R mutant which could require KRAS “ON” drugs.”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [88]
Specific KRAS variants can have tissue-specific oncogenic effects and exhibit allele-specific therapeutic vulnerabilities in downstream effector pathways.
“The implication of these unusual variants is that specific KRAS variants can have tissue-specific oncogenic effects and exhibit allele-specific therapeutic vulnerabilities in downstream effector pathways.”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [88]
The KRASG12R oncoprotein has distinct biochemical properties and is less effective at activating PI3K signaling and macropinocytosis.
“although evidence suggests that the KRASG12R oncoprotein has distinct biochemical properties and is less effective at activating PI3K signaling and micropinocytosis (54).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [54]
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References 67 · Cited by 231
Research works printed but not linked: 1
- [59]Xds Kabsch W. Acta Crystallogr D Biol Crystallogr 2010; 66: 125– 32. 20124692 PMC2815665
- Authors
- Hobbs, G. A., Baker, N. M., Miermont, A. M., Thurman, R. D., Pierobon, M., Tran, T. H., Anderson, A. O., Waters, A. M., Diehl, J. N., Papke, B., Hodge, R. G., Klomp, J. E., Goodwin, C. M., DeLiberty, J. M., Wang, J., Ng, R. W. S., Gautam, P., Bryant, K. L., Esposito, D., Campbell, S. L., Petricoin, E. F., Simanshu, D. K., Aguirre, A. J., Wolpin, B. M., Wennerberg, K., Rudloff, U., Cox, A. D., & Der, C. J.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- National Cancer Institute (US)
- George Mason University (US)
- Frederick National Laboratory for Cancer Research (US)
- Dana-Farber Cancer Institute (US)
- University of Helsinki (FI)
- Broad Institute (US)
- University of Copenhagen (DK)
- Corresponding author
- Rudloff, Udo
- Der, Channing J.
- ORCID
- Hobbs, G. Aaron
- Baker, Nicole M.
- Miermont, Anne M.
- Pierobon, Mariaelena
- Tran, Timothy H.
- Waters, Andrew M.
- Diehl, J. Nathaniel
- Papke, Bjoern
- Hodge, Richard G.
- Klomp, Jennifer E.
- Goodwin, Craig M.
- DeLiberty, Jonathan M.
- Ng, Raymond W.S.
- Gautam, Prson
- Bryant, Kirsten L.
- Esposito, Dominic
- Campbell, Sharon L.
- Petricoin, Emanuel F.
- Simanshu, Dhirendra K.
- Aguirre, Andrew J.
- Wolpin, Brian M.
- Wennerberg, Krister
- Rudloff, Udo
- Cox, Adrienne D.
- Der, Channing J.
- Venue
- Cancer Discovery
- Published
- 2020-01-01
- Volume
- 10
- Issue
- 1
- Pages
- 104-123
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6954322
- OpenAlex
- W2981746321
- Cited by
- 231
- References
- 67
- Citations by year
- 2026: 33 · 2025: 38 · 2024: 32 · 2023: 25 · 2022: 49 · 2021: 33 · 2020: 20 · 2019: 1
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- other-oa
- Locations
- Cancer Discovery (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, other-oa)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- HHS | NIH | National Cancer Institute (R01CA42978, U01CA199235, P50CA196510, R35CA232113, P01CA203657, K08CA218420-02, P50CA127003, U01CA224146, F32CA200313, T32CA009156, F31CA180628, F32CA221005, T32CA071341, ZIA BC 011267, HHSN261200800001E, P30CA016086)
- DOD (W81XWH-15-1-0611)
- Lustgarten Foundation (388222)
- Pancreatic Cancer Action Network (15-90-25-DER, 18-35-AGUI)
- Doris Duke Charitable Foundation (2017066)
- American Association for Cancer Research (18-40-41-HODG)
- American Cancer Society (PF-18-061)
- Deutsche Forschungsgemeinschaft (DFG PA 3051/1-1)
- Slomo and Cindy Silvian Foundation
- DFCI Hale Family Center for Pancreatic Cancer Research
- Dana-Farber Cancer Institute Hale Center for Pancreatic Cancer Research
- Pancreatic Cancer Action Network/AACR Pathway to Leadership
- HHS | NIH | National Institute of Allergy and Infectious Diseases (5P30AI050410)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- pancreatic ductal adenocarcinoma, macropinocytosis, PI3K signaling, PI3Kγ, c-Myc, ERK inhibition, autophagy inhibition, drug sensitivity
- MeSH terms
- Animals, Female, Humans, Mutation, Pancreatic Neoplasms, Pinocytosis, Tumor Cells, Cultured, Biomarkers, Tumor, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Apoptosis, Carcinoma, Pancreatic Ductal, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Class I Phosphatidylinositol 3-Kinases
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