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

Thomas R. Cox, Mar 2019

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

We have just published a new paper in Breast Cancer Research in collaboration with lead researcher Dr. David Croucher from the Garvan Institute, looking at how and why ERBB2 (HER2) positive breast cancer cells develop resistance to targeted therapies such as trastuzumab (Herceptin™).

 

doi.org/10.1186/s13058-019-1127-y

Antibody-mediated targeting of HER2 has been a cornerstone of treatment for HER2-amplified breast cancer patients for two decades. However, the lack of response in some patients and the rapid onset of relapse in many patients has led us to question how and why this happens.

Using a systematic protein-protein interaction screen (where we look at all the different molecules that the HER2 protein interacts with), combined with computational approaches, we have found a series of new receptor-tyrosine-kinases (molecules on the surface of breast cancer cells that activate pathways controlling things like cell growth). These newly identified interactions with HER2 are responsible for altering the efficacy of trastuzumab (Herceptin™) – and pertuzumab (Perjeta™)-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines.

Our findings demonstrate that the combination of pertuzumab and lapatinib represents a novel rationalised combination therapy which based upon a mechanistic understanding of the patho-physiological formation of non-canonical ERBB2 heterodimers. The synergistic combination of these drugs in cell lines resistant to the combination of pertuzumab and trastuzumab, suggests that further clinical investigation is warranted in patients that do not respond to either single antibody therapy or the combination of pertuzumab and trastuzumab.

Abstract

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.

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.

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.

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.

Links

View the abstract in PubMed
View the article on the Breast Cancer Research website

Citation

Kennedy SP et al. Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer
Breast Cancer Research (2019) | doi: 10.1186/s13058-019-1127-y

Key words

Breast Cancer, ERBB2, HER2, Pertuzumab, Heterodimers, Receptor tyrosine kinases

Funding

DRC is a Cancer Institute NSW Fellow, a National Breast Cancer Foundation Fellow and was previously a Science Foundation Ireland/Marie Curie Actions Fellow. WK was supported by an Irish Cancer Society CCRC BREAST-PREDICT grant (CCRC13GAL). The research findings presented in this manuscript were funded by Science Foundation Ireland (14/IA/2395) and Science Foundation Ireland – Marie Curie Actions COFUND (11/SIRG/B2157) and Cancer Institute NSW (13/FRL/1-02). JFH, KJM, JW and RS were recipients of an Australian Postgraduate Award.