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Breast Cancer Research
Published in: Breast Cancer Research 1/2019

Open Access 01-12-2019 | Breast Cancer | Research article

Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer

Authors: Sean P. Kennedy, Jeremy Z. R. Han, Neil Portman, Max Nobis, Jordan F. Hastings, Kendelle J. Murphy, Sharissa L. Latham, Antonia L. Cadell, Dushan Miladinovic, Gabriella R. Marriott, Yolande E. I. O’Donnell, Robert F. Shearer, James T. Williams, Amaya Garcia Munoz, Thomas R. Cox, D. Neil Watkins, Darren N. Saunders, Paul Timpson, Elgene Lim, Walter Kolch, David R. Croucher

Published in: Breast Cancer Research | Issue 1/2019

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Abstract

Background

The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies.

Methods

Through a systematic protein-protein interaction screen, we have identified and validated alternative RTKs that interact with ERBB2. Using quantitative readouts of signalling pathway activation and cell proliferation, we have examined their influence upon the mechanism of trastuzumab- and pertuzumab-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines and a patient-derived xenograft model.

Results

We now demonstrate that inactivation of ERBB3/PI3K by these therapeutic antibodies is insufficient to inhibit the growth of ERBB2-amplified breast cancer cells. Instead, we show extensive promiscuity between ERBB2 and an array of RTKs from outside of the EGFR family. Paradoxically, pertuzumab also acts as an artificial ligand to promote ERBB2 activation and ERK signalling, through allosteric activation by a subset of these non-canonical RTKs. However, this unexpected activation mechanism also increases the sensitivity of the receptor network to the ERBB2 kinase inhibitor lapatinib, which in combination with pertuzumab, displays a synergistic effect in single-agent resistant cell lines and PDX models.

Conclusions

The interaction of ERBB2 with a number of non-canonical RTKs activates a compensatory signalling response following treatment with pertuzumab, although a counter-intuitive combination of ERBB2 antibody therapy and a kinase inhibitor can overcome this innate therapeutic resistance.
Appendix
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Metadata
Title
Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer
Authors
Sean P. Kennedy
Jeremy Z. R. Han
Neil Portman
Max Nobis
Jordan F. Hastings
Kendelle J. Murphy
Sharissa L. Latham
Antonia L. Cadell
Dushan Miladinovic
Gabriella R. Marriott
Yolande E. I. O’Donnell
Robert F. Shearer
James T. Williams
Amaya Garcia Munoz
Thomas R. Cox
D. Neil Watkins
Darren N. Saunders
Paul Timpson
Elgene Lim
Walter Kolch
David R. Croucher
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2019
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-019-1127-y

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