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

• Published in: Breast cancer research : BCR Vol. 21; no. 1; p. 43
• Main Authors: Kennedy, Sean P, Han, Jeremy Z R, Portman, Neil, Nobis, Max, Hastings, Jordan F, Murphy, Kendelle J, Latham, Sharissa L, Cadell, Antonia L, Miladinovic, Dushan, Marriott, Gabriella R, O'Donnell, Yolande E I, Shearer, Robert F, Williams, James T, Munoz, Amaya Garcia, Cox, Thomas R, Watkins, D Neil, Saunders, Darren N, Timpson, Paul, Lim, Elgene, Kolch, Walter, Croucher, David R
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 21.03.2019; BioMed Central; BMC
• Subjects: 1-Phosphatidylinositol 3-kinase; Allosteric properties; Animals; Antibodies; Antibodies, Monoclonal, Humanized - pharmacology; Biomarkers; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer cells; Cancer patients; Cancer therapies; Cell activation; Cell culture; Cell Line, Tumor; Cell proliferation; Chemotherapy; Clinical trials; Dimerization; Disease Models, Animal; Displays (Marketing); Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Drug therapy; Enzyme inhibitors; Epidermal growth factor; Epidermal growth factor receptors; ErbB-2 protein; ErbB-3 protein; ERBB2; Extracellular signal-regulated kinase; Family relations; Female; Fluorescent Antibody Technique; Heterodimers; Humans; Immunoglobulins; Immunohistochemistry; Immunotherapy; Kinases; Lapatinib; Ligands; Medical prognosis; Metastasis; Mice; Monoclonal antibodies; Patients; Pertuzumab; Phenols (Class of compounds); Phosphorylation; Promiscuity; Protein interaction; Protein Kinase Inhibitors - pharmacology; Protein Multimerization; Protein-protein interactions; Protein-tyrosine kinase receptors; Receptor tyrosine kinases; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - chemistry; Receptor, ErbB-2 - metabolism; Signal transduction; Signal Transduction - drug effects; Targeted cancer therapy; Trastuzumab; Trastuzumab - pharmacology; Tumor cell lines; Tyrosine; Xenograft Model Antitumor Assays; Xenografts; United States > US; Heterodimers; Breast cancer; Pertuzumab; Receptor tyrosine kinases; ERBB2
• ISSN: 1465-542X; 1465-5411; 1465-542X
• DOI: 10.1186/s13058-019-1127-y

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.