Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

Stephen R Adams; Howard C Yang; Elamprakash N Savariar; Joe Aguilera; Jessica L Crisp; Karra A Jones; Michael A Whitney; Scott M Lippman; Ezra E W Cohen; Roger Y Tsien; Sunil J Advani

doi:10.1038/ncomms13019

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Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

Journal article

Open access

Peer reviewed

Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize

Stephen R Adams, Howard C Yang, Elamprakash N Savariar, Joe Aguilera, Jessica L Crisp, Karra A Jones, Michael A Whitney, Scott M Lippman, Ezra E W Cohen, Roger Y Tsien, …

Nature communications, Vol.7(1), pp.13019-13019

10/04/2016

DOI: 10.1038/ncomms13019

PMCID: PMC5059467

PMID: 27698471

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Abstract

Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery.

Neoplasm Transplantation

Receptor, Epidermal Growth Factor - immunology

Signal Transduction

Cell Survival

Maytansine - analogs & derivatives

Tubulin Modulators - pharmacology

Humans

Radiation-Sensitizing Agents - pharmacology

Drug Resistance, Neoplasm

Maytansine - pharmacology

Neoplasms - drug therapy

Animals

Mice, Nude

Aminobenzoates - pharmacology

Cell Line, Tumor

Female

Neoplasms - radiotherapy

Mice

Trastuzumab - pharmacology

Oligopeptides - pharmacology

Radiation, Ionizing

Details

Title: Subtitle: Anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize
Creators: Stephen R Adams - Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA
Howard C Yang - Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California 92093, USA
Elamprakash N Savariar - Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA
Joe Aguilera - Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, California 92093, USA
Jessica L Crisp - Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA
Karra A Jones - Department of Pathology, University of California San Diego, La Jolla, California 92093, USA
Michael A Whitney - Department of Pharmacology, University of California San Diego, La Jolla, California 92093, USA
Scott M Lippman - UC San Diego, Moores Cancer Center, La Jolla, California 92093, USA
Ezra E W Cohen - UC San Diego, Moores Cancer Center, La Jolla, California 92093, USA
Roger Y Tsien - Department of Chemistry and Biochemistry and Howard Hughes Medical Institute, University of California San Diego, La Jolla, California 92093, USA
Sunil J Advani - UC San Diego, Moores Cancer Center, La Jolla, California 92093, USA
Resource Type: Journal article
Publication Details: Nature communications, Vol.7(1), pp.13019-13019
DOI: 10.1038/ncomms13019
PMID: 27698471
PMCID: PMC5059467
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: R01 CA158448 / NCI NIH HHS R21 CA205765 / NCI NIH HHS
Language: English
Date published: 10/04/2016
Academic Unit: Pathology
Record Identifier: 9984047754402771

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