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Tumor Microenvironment and Immunobiology

Cyclophilin A Inhibitor Debio-025 Targets Crk, Reduces Metastasis, and Induces Tumor Immunogenicity in Breast Cancer

Viralkumar Davra, Tamjeed Saleh, Ke Geng, Stanley Kimani, Dhriti Mehta, Canan Kasikara, Brendan Smith, Nicholas W. Colangelo, Bryan Ciccarelli, Hong Li, Edouard I. Azzam, Charalampos G. Kalodimos, Raymond B. Birge and Sushil Kumar
Viralkumar Davra
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Tamjeed Saleh
2Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
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Ke Geng
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Stanley Kimani
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Dhriti Mehta
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Canan Kasikara
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Brendan Smith
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Nicholas W. Colangelo
3Department of Radiology, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Bryan Ciccarelli
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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Hong Li
4Center for Advanced Proteomics, Rutgers University, Newark, New Jersey.
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Edouard I. Azzam
3Department of Radiology, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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  • ORCID record for Edouard I. Azzam
Charalampos G. Kalodimos
2Department of Structural Biology, St Jude Children's Research Hospital, Memphis, Tennessee.
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Raymond B. Birge
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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  • For correspondence: sushil_kumar@dfci.harvard.edu birgera@njms.rutgers.edu
Sushil Kumar
1Department of Microbiology, Biochemistry and Molecular Genetics, Center for Cell Signaling, Rutgers- New Jersey Medical School, Newark, New Jersey.
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  • For correspondence: sushil_kumar@dfci.harvard.edu birgera@njms.rutgers.edu
DOI: 10.1158/1541-7786.MCR-19-1144 Published August 2020
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Abstract

The Crk adaptor protein, a critical modifier of multiple signaling pathways, is overexpressed in many cancers where it contributes to tumor progression and metastasis. Recently, we have shown that Crk interacts with the peptidyl prolyl cis-trans isomerase, Cyclophilin A (CypA; PP1A) via a G219P220Y221 (GPY) motif in the carboxyl-terminal linker region of Crk, thereby delaying pY221 phosphorylation and preventing downregulation of Crk signaling. Here, we investigate the physiologic significance of the CypA/Crk interaction and query whether CypA inhibition affects Crk signaling in vitro and in vivo. We show that CypA, when induced under conditions of hypoxia, regulates Crk pY221 phosphorylation and signaling in cancer cell lines. Using nuclear magnetic resonance spectroscopy, we show that CypA binds to the Crk GPY motif via the catalytic PPII domain of CypA, and small-molecule nonimmunosuppressive inhibitors of CypA (Debio-025) disrupt the CypA–CrkII interaction and restores phosphorylation of Crk Y221. In cultured cell lines, Debio-025 suppresses cell migration, and when administered in vivo in an orthotopic model of triple-negative breast cancer, Debio-025 showed antitumor efficacy either alone or in combination with anti-PD-1 mAb, reducing both tumor volume and metastatic lung dispersion. Furthermore, when analyzed by NanoString immune profiling, treatment of Debio-025 with anti-PD-1 mAb increased both T-cell signaling and innate immune signaling in tumor microenvironment.

Implications: These data suggest that pharmacologic inhibition of CypA may provide a promising and unanticipated consequence in cancer biology, in part by targeting the CypA/CrkII axis that regulates cell migration, tumor metastasis, and host antitumor immune evasion.

Footnotes

  • Mol Cancer Res 2020;18:1189–201

  • Received November 27, 2019.
  • Revision received March 18, 2020.
  • Accepted April 17, 2020.
  • Published first April 22, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (8)
August 2020
Volume 18, Issue 8
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Cyclophilin A Inhibitor Debio-025 Targets Crk, Reduces Metastasis, and Induces Tumor Immunogenicity in Breast Cancer
Viralkumar Davra, Tamjeed Saleh, Ke Geng, Stanley Kimani, Dhriti Mehta, Canan Kasikara, Brendan Smith, Nicholas W. Colangelo, Bryan Ciccarelli, Hong Li, Edouard I. Azzam, Charalampos G. Kalodimos, Raymond B. Birge and Sushil Kumar
Mol Cancer Res August 1 2020 (18) (8) 1189-1201; DOI: 10.1158/1541-7786.MCR-19-1144

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Cyclophilin A Inhibitor Debio-025 Targets Crk, Reduces Metastasis, and Induces Tumor Immunogenicity in Breast Cancer
Viralkumar Davra, Tamjeed Saleh, Ke Geng, Stanley Kimani, Dhriti Mehta, Canan Kasikara, Brendan Smith, Nicholas W. Colangelo, Bryan Ciccarelli, Hong Li, Edouard I. Azzam, Charalampos G. Kalodimos, Raymond B. Birge and Sushil Kumar
Mol Cancer Res August 1 2020 (18) (8) 1189-1201; DOI: 10.1158/1541-7786.MCR-19-1144
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