Abstract
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that efficiently delivers a highly potent microtubule inhibitor to HER2 overexpressing cells. Herein, we utilize HER2 transformed human mammary epithelial cells (HME2) to demonstrate in vitro and in vivo response and recurrence upon T-DM1 treatment. Continuous in vitro dosing of HME2 cells with T-DM1 failed to produce a spontaneously resistant cell line. However, induction of epithelial–mesenchymal transition (EMT) via pretreatment with TGF-β1 was capable of promoting emergence of T-DM1-resistant (TDM1R) cells. Flow cytometric analyses indicated that induction of EMT decreased trastuzumab binding, prior to overt loss of HER2 expression in TDM1R cells. Kinome analyses of TDM1R cells indicated increased phosphorylation of ErbB1, ErbB4, and FGFR1. TDM1R cells failed to respond to the ErbB kinase inhibitors lapatinib and afatinib, but they acquired sensitivity to FIIN4, a covalent FGFR kinase inhibitor. In vivo, minimal residual disease (MRD) remained detectable via bioluminescent imaging following T-DM1-induced tumor regression. Upon cessation of the ADC, relapse occurred and secondary tumors were resistant to additional rounds of T-DM1. These recurrent tumors could be inhibited by FIIN4. Moreover, ectopic overexpression of FGFR1 was sufficient to enhance tumor growth, diminish trastuzumab binding, and promote recurrence following T-DM1-induced MRD. Finally, patient-derived xenografts from a HER2+ breast cancer patient who had progressed on trastuzumab failed to respond to T-DM1, but tumor growth was significantly inhibited by FIIN4. Overall, our studies strongly support therapeutic combination of TDM1 with FGFR-targeted agents in HER2+ breast cancer.
Highlights
Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases
Upon further investigation into the potential of these receptors in facilitating resistance to T-DM1, we found that the expression level of fibroblast growth factor receptor 1 (FGFR1) induced by TGF-β was further enhanced upon acquisition of T-DM1 resistance (Fig. 3C)
Following disease progression on trastuzumab/pertuzumab, HER2+ patients can be treated with T-DM1, trastuzumab-deruxtecan, lapatinib, neratinib, tucatinib, or various combinations thereof
Summary
Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases. HER2-amplified breast cancers respond to treatment with the HER2-targeted monoclonal antibodies pertuzumab and trastuzumab at a high rate, but acquired resistance to these therapies remains a major clinical problem for patients with this breast cancer subtype. Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) that provides a mechanism to deliver a potent microtubuletargeting cytotoxin to HER2 overexpressing cells. While several more recent trials have found T-DM1 to be effect in the later line settings, disease recurrence and progression is still a major clinical issue. These data suggest that there are uncharacterized drivers of resistance at play[3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
