KRAS is the most frequently mutated human oncogene, and KRAS inhibition has been a longtime goal. Recently, inhibitors were developed that bind KRASG12C-GDP and react with Cys-12 (G12C-Is). Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that an SHP2 inhibitor (SHP2-I) increases KRAS-GDP occupancy, enhancing G12C-I efficacy. The SHP2-I abrogated RTK feedback signaling and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRASG12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non–small cell lung cancer (NSCLC). SHP2-I/G12C-I combination evoked favorable but tumor site–specific changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using cells expressing inhibitor-resistant SHP2 showed that SHP2 inhibition in PDAC cells is required for PDAC regression and remodeling of the immune microenvironment but revealed direct inhibitory effects on tumor angiogenesis and vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies.
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4 January 2021
Article|
October 08 2020
SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling
Carmine Fedele,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Carmine Fedele: carmine.fedele@nyulangone.org
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Shuai Li,
Conceptualization, Data curation, Formal analysis, Investigation, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Kai Wen Teng,
Kai Wen Teng
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Connor J.R. Foster,
Connor J.R. Foster
Formal analysis, Investigation, Project administration, Resources, Validation, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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David Peng,
David Peng
Data curation, Formal analysis, Investigation, Resources, Visualization
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Hao Ran,
Hao Ran
Conceptualization, Data curation
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Paolo Mita,
Paolo Mita
Methodology, Resources, Writing - review & editing
2
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY
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Mitchell J. Geer,
Mitchell J. Geer
Investigation, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Takamitsu Hattori,
Takamitsu Hattori
Formal analysis, Investigation, Methodology, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
6
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY
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Akiko Koide,
Akiko Koide
Formal analysis, Investigation, Methodology, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
3
Department of Medicine, New York University School of Medicine, NYU Langone Health, New York, NY
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Yubao Wang,
Yubao Wang
Investigation
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Kwan Ho Tang,
Kwan Ho Tang
Investigation, Methodology
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Joshua Leinwand,
Joshua Leinwand
Investigation, Writing - review & editing
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
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Wei Wang,
Wei Wang
Methodology, Writing - review & editing
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
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Brian Diskin,
Brian Diskin
Investigation
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
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Jiehui Deng,
Jiehui Deng
Resources
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Ting Chen,
Ting Chen
Resources
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Igor Dolgalev,
Igor Dolgalev
Formal analysis, Methodology, Software, Visualization
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
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Ugur Ozerdem,
Ugur Ozerdem
Investigation, Writing - original draft, Writing - review & editing
5
Department of Pathology, New York University School of Medicine, NYU Langone Health, New York, NY
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George Miller,
George Miller
Supervision
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
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Shohei Koide,
Shohei Koide
Methodology, Project administration, Resources, Supervision, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
6
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY
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Kwok-Kin Wong,
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Kwok-Kin Wong: kwok-kin.wong@nyulangone.org
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Benjamin G. Neel
Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Correspondence to Benjamin G Neel: benjamin.neel@nyulangone.org
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Carmine Fedele
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Shuai Li
Conceptualization, Data curation, Formal analysis, Investigation, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Kai Wen Teng
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Validation, Visualization, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Connor J.R. Foster
Formal analysis, Investigation, Project administration, Resources, Validation, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
David Peng
Data curation, Formal analysis, Investigation, Resources, Visualization
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Hao Ran
Conceptualization, Data curation
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Paolo Mita
Methodology, Resources, Writing - review & editing
2
Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY
Mitchell J. Geer
Investigation, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Takamitsu Hattori
Formal analysis, Investigation, Methodology, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
6
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY
Akiko Koide
Formal analysis, Investigation, Methodology, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
3
Department of Medicine, New York University School of Medicine, NYU Langone Health, New York, NY
Yubao Wang
Investigation
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Kwan Ho Tang
Investigation, Methodology
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Joshua Leinwand
Investigation, Writing - review & editing
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
Wei Wang
Methodology, Writing - review & editing
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
Brian Diskin
Investigation
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
Jiehui Deng
Resources
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Ting Chen
Resources
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Igor Dolgalev
Formal analysis, Methodology, Software, Visualization
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Ugur Ozerdem
Investigation, Writing - original draft, Writing - review & editing
5
Department of Pathology, New York University School of Medicine, NYU Langone Health, New York, NY
George Miller
Supervision
4
S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, NY
Shohei Koide
Methodology, Project administration, Resources, Supervision, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
6
Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, NY
Kwok-Kin Wong
Supervision, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
Benjamin G. Neel
Conceptualization, Funding acquisition, Methodology, Project administration, Supervision, Writing - original draft, Writing - review & editing
1
Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, NY
*
C. Fedele and S. Li contributed equally to this paper.
Carmine Fedele: carmine.fedele@nyulangone.org
Kwok-Kin Wong: kwok-kin.wong@nyulangone.org
Correspondence to Benjamin G Neel: benjamin.neel@nyulangone.org
Received:
July 03 2020
Revision Received:
August 04 2020
Accepted:
August 20 2020
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
American Cancer Society
(132652-PF-18-180-01-TBE)
National Institutes of Health
(P30CA016087, CA49152, CA219670, CA194864, P30 CA016087)
© 2020 Fedele et al.
2020
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (1): e20201414.
Article history
Received:
July 03 2020
Revision Received:
August 04 2020
Accepted:
August 20 2020
Citation
Carmine Fedele, Shuai Li, Kai Wen Teng, Connor J.R. Foster, David Peng, Hao Ran, Paolo Mita, Mitchell J. Geer, Takamitsu Hattori, Akiko Koide, Yubao Wang, Kwan Ho Tang, Joshua Leinwand, Wei Wang, Brian Diskin, Jiehui Deng, Ting Chen, Igor Dolgalev, Ugur Ozerdem, George Miller, Shohei Koide, Kwok-Kin Wong, Benjamin G. Neel; SHP2 inhibition diminishes KRASG12C cycling and promotes tumor microenvironment remodeling. J Exp Med 4 January 2021; 218 (1): e20201414. doi: https://doi.org/10.1084/jem.20201414
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