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Translational Science

Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer

Munisha Smalley, Siva Kumar Natarajan, Jayanta Mondal, Douglas Best, David Goldman, Basavaraja Shanthappa, Moriah Pellowe, Chinmayee Dash, Tanmoy Saha, Sachin Khiste, Nithya Ramadurai, Elliot O. Eton, Joshua L. Smalley, Andrew Brown, Allen Thayakumar, Mamunur Rahman, Kazuya Arai, Mohammad Kohandel, Shiladitya Sengupta and Aaron Goldman
Munisha Smalley
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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Siva Kumar Natarajan
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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Jayanta Mondal
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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Douglas Best
2Integrative Immuno-Oncology Center, Farcast Biosciences, Woburn, Massachusetts.
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David Goldman
37730 Blackcrest Pl, Tucson, Arizona.
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Basavaraja Shanthappa
2Integrative Immuno-Oncology Center, Farcast Biosciences, Woburn, Massachusetts.
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Moriah Pellowe
4Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada.
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  • ORCID record for Moriah Pellowe
Chinmayee Dash
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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  • ORCID record for Chinmayee Dash
Tanmoy Saha
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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Sachin Khiste
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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Nithya Ramadurai
2Integrative Immuno-Oncology Center, Farcast Biosciences, Woburn, Massachusetts.
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Elliot O. Eton
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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  • ORCID record for Elliot O. Eton
Joshua L. Smalley
5Tufts Medical School, Boston, Massachusetts.
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Andrew Brown
6Division of Computational Genomics, Arrayo, Boston, Massachusetts.
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Allen Thayakumar
2Integrative Immuno-Oncology Center, Farcast Biosciences, Woburn, Massachusetts.
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Mamunur Rahman
7Medical and Biological Laboratories International, Woburn, Massachusetts.
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Kazuya Arai
8JSR Life Sciences, Minato-ku, Tokyo, Japan.
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Mohammad Kohandel
4Department of Applied Mathematics, University of Waterloo, Waterloo, Ontario, Canada.
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Shiladitya Sengupta
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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  • For correspondence: goldman1@mit.edu shiladit@mit.edu
Aaron Goldman
1Division of Engineering in Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
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  • For correspondence: goldman1@mit.edu shiladit@mit.edu
DOI: 10.1158/0008-5472.CAN-19-4036 Published December 2020
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Abstract

Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here, we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatiotemporally controlled nanomedicines, which boost therapeutic efficacy and invigorate “disabled” NK cells. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, NK group 2 member D, and MHC class I polypeptide-related sequence A, B. Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. On the basis of this evidence, we engineered a “chimeric” nanotherapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally reprimes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically approved agents. These findings highlight a convergence between drug-induced resistance, the tumor immune contexture, and engineered approaches that consider the tumor and microenvironment to improve the success of combinatorial therapy.

Significance: This study uncovers a molecular mechanism linking drug-induced resistance and tumor immunity and provides novel engineered solutions that target these mechanisms in the tumor and improve immunity, thus mitigating off-target effects.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

  • Cancer Res 2020;80:5355–66

  • Received December 29, 2019.
  • Revision received August 16, 2020.
  • Accepted October 9, 2020.
  • Published first October 19, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Research: 80 (23)
December 2020
Volume 80, Issue 23
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Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer
Munisha Smalley, Siva Kumar Natarajan, Jayanta Mondal, Douglas Best, David Goldman, Basavaraja Shanthappa, Moriah Pellowe, Chinmayee Dash, Tanmoy Saha, Sachin Khiste, Nithya Ramadurai, Elliot O. Eton, Joshua L. Smalley, Andrew Brown, Allen Thayakumar, Mamunur Rahman, Kazuya Arai, Mohammad Kohandel, Shiladitya Sengupta and Aaron Goldman
Cancer Res December 1 2020 (80) (23) 5355-5366; DOI: 10.1158/0008-5472.CAN-19-4036

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Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer
Munisha Smalley, Siva Kumar Natarajan, Jayanta Mondal, Douglas Best, David Goldman, Basavaraja Shanthappa, Moriah Pellowe, Chinmayee Dash, Tanmoy Saha, Sachin Khiste, Nithya Ramadurai, Elliot O. Eton, Joshua L. Smalley, Andrew Brown, Allen Thayakumar, Mamunur Rahman, Kazuya Arai, Mohammad Kohandel, Shiladitya Sengupta and Aaron Goldman
Cancer Res December 1 2020 (80) (23) 5355-5366; DOI: 10.1158/0008-5472.CAN-19-4036
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