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SHP2 Inhibition Abrogates Adaptive Resistance to KRASG12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors

Carmine Fedele, Shuai Li, Kai Wen Teng, Connor Foster, David Peng, Hao Ran, Paolo Mita, Mitchell Geer, Takamitsu Hattori, Akiko Koide, Yubao Wang, Kwan H. 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
doi: https://doi.org/10.1101/2020.05.30.125138
Carmine Fedele
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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  • For correspondence: Benjamin.Neel@nyulangone.org Kwok-Kin.Wong@nyulangone.org Carmine.Fedele@nyulangone.org
Shuai Li
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Kai Wen Teng
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Connor Foster
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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David Peng
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Hao Ran
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Paolo Mita
2Institute for Systems Genetics and Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, New York
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Mitchell Geer
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Takamitsu Hattori
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Akiko Koide
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
3Department of Medicine, New York University School of Medicine, NYU Langone Health, New York, New York
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Yubao Wang
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Kwan H. Tang
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Joshua Leinwand
4S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, New York
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Wei Wang
4S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, New York
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Brian Diskin
4S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, NYU Langone Health, New York, New York
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Jiehui Deng
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Ting Chen
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Igor Dolgalev
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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Ugur Ozerdem
5Department of Pathology, New York University School of Medicine, NYU Langone Health, New York, New York
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George Miller
3Department of Medicine, New York University School of Medicine, NYU Langone Health, New York, New York
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Shohei Koide
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
6Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, NYU Langone Health, New York, New York
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Kwok-Kin Wong
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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  • For correspondence: Benjamin.Neel@nyulangone.org Kwok-Kin.Wong@nyulangone.org Carmine.Fedele@nyulangone.org
Benjamin G. Neel
1Laura and Isaac Perlmutter Cancer Center, New York University School of Medicine, NYU Langone Health, New York, New York
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  • For correspondence: Benjamin.Neel@nyulangone.org Kwok-Kin.Wong@nyulangone.org Carmine.Fedele@nyulangone.org
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ABSTRACT

KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime therapeutic goal. Recently, inhibitors (G12C-Is) that bind KRASG12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRASG12C activation and inhibitor engagement, we found that, reflecting its action upstream of SOS1/2, SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and blocked 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) models. Biochemical analysis revealed enhanced suppression of ERK-, MYC-, anti-apoptotic-, and cell-cycle genes, and increased pro-apoptotic gene expression in tumors from combination-treated mice. SHP2-I/G12C-I also evoked favorable 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 tumor regression and remodeling of the immune microenvironment, but also revealed direct inhibitory effects on angiogenesis resulting in decreased tumor vascularity. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional combination strategies for enhancing the efficacy of G12C-Is.

Competing Interest Statement

B.G.N. is a co-founder, chair of the Scientific Advisory Board, and holds equity in Navire Pharmaceuticals, which is developing SHP2 inhibitors for cancer therapy. He also is co-founder and holds equity in Northern Biologics, consults and has equity in Arvinas, Inc., and is an expert witness for Johnson and Johnson. His spouse holds equity in Arvinas, Gilead, Regeneron, Moderna, and Amgen, the latter of which developed AMG-510. K.K.W. is an equity holder of G1 Therapeutics, Zentalis and Epiphanes and he has consulting/sponsored research agreements with the following: AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono, and Array (consulting & sponsored research); MedImmune, Mirati, Takeda, TargImmune, and BMS (sponsored research only).

Footnotes

  • Financial Support: This work was supported by R01CA49152, R01CA219670, R01CA194864, Cancer Center Core Grant P30 CA016087 and a Sponsored Research Agreement with Mirati Therapeutics.

  • Conflicts of Interest: B.G.N. is a co-founder, chair of the Scientific Advisory Board, and holds equity in Navire Pharmaceuticals, which is developing SHP2 inhibitors for cancer therapy. He also is co-founder and holds equity in Northern Biologics, consults and has equity in Arvinas, Inc., and is an expert witness for Johnson and Johnson. His spouse holds equity in Arvinas, Gilead, Regeneron, Moderna, and Amgen, the latter of which developed AMG-510. K.K.W. is an equity holder of G1 Therapeutics, Zentalis and Epiphanes and he has consulting/sponsored research agreements with the following: AstraZeneca, Janssen, Pfizer, Novartis, Merck, Ono, and Array (consulting & sponsored research); MedImmune, Mirati, Takeda, TargImmune, and BMS (sponsored research only).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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SHP2 Inhibition Abrogates Adaptive Resistance to KRASG12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors
Carmine Fedele, Shuai Li, Kai Wen Teng, Connor Foster, David Peng, Hao Ran, Paolo Mita, Mitchell Geer, Takamitsu Hattori, Akiko Koide, Yubao Wang, Kwan H. 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
bioRxiv 2020.05.30.125138; doi: https://doi.org/10.1101/2020.05.30.125138
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SHP2 Inhibition Abrogates Adaptive Resistance to KRASG12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors
Carmine Fedele, Shuai Li, Kai Wen Teng, Connor Foster, David Peng, Hao Ran, Paolo Mita, Mitchell Geer, Takamitsu Hattori, Akiko Koide, Yubao Wang, Kwan H. 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
bioRxiv 2020.05.30.125138; doi: https://doi.org/10.1101/2020.05.30.125138

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