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Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast
Sean P Kennedy1,2, Jeremy Z R Han1, Neil Portman1,3
1The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, Sydney, NSW, 2010, Australia.
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.
Insights
Antibody therapies targeting ERBB2/ERBB3 signaling are insufficient for ERBB2-amplified breast cancer. New research reveals alternative RTK interactions that drive resistance, but combining ERBB2 antibody therapy with kinase inhibitors shows synergistic effects.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The ERBB2/ERBB3/PI3K pathway is a validated target in ERBB2-amplified breast cancer.
- Current antibody therapies targeting this axis have limitations, including lack of response and rapid relapse.
Purpose of the Study:
- To identify alternative receptor tyrosine kinases (RTKs) interacting with ERBB2.
- To investigate the impact of these interactions on therapeutic response to ERBB2-targeted antibodies.
- To explore novel combination strategies for overcoming treatment resistance.
Main Methods:
- Systematic protein-protein interaction screening to identify ERBB2-interacting RTKs.
- Quantitative analysis of signaling pathway activation and cell proliferation.
- Evaluation of therapeutic efficacy in ERBB2-amplified breast cancer cell lines and patient-derived xenograft (PDX) models.
Main Results:
- ERBB2 interacts with non-EGFR family RTKs, leading to compensatory signaling.
- Pertuzumab can paradoxically promote ERBB2 activation and ERK signaling via non-canonical RTKs.
- Combination therapy with pertuzumab and lapatinib demonstrates synergistic effects against resistant models.
Conclusions:
- ERBB2-amplified breast cancer exhibits resistance mechanisms involving non-canonical RTK interactions.
- Targeting ERBB2/ERBB3 alone is insufficient to overcome resistance.
- Combined ERBB2 antibody and kinase inhibitor therapy offers a promising strategy to overcome therapeutic resistance.
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