Journal article
Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy
NPJ breast cancer, Vol.7(1), pp.5-5
01/21/2021
DOI: 10.1038/s41523-020-00213-5
PMCID: 7820437
PMID: 33479246
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-beta 1 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.
Details
- Title: Subtitle
- Fibroblast growth factor receptor facilitates recurrence of minimal residual disease following trastuzumab emtansine therapy
- Creators
- Saeed S. Akhand - Purdue University West LafayetteHao Chen - Purdue University West LafayetteStephen Connor Purdy - Purdue University West LafayetteZian Liu - Purdue University West LafayetteJoshua C. Anderson - University of Alabama at BirminghamChristopher D. Willey - University of Alabama at BirminghamMichael K. Wendt - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- NPJ breast cancer, Vol.7(1), pp.5-5
- DOI
- 10.1038/s41523-020-00213-5
- PMID
- 33479246
- PMCID
- 7820437
- NLM abbreviation
- NPJ Breast Cancer
- ISSN
- 2374-4677
- eISSN
- 2374-4677
- Publisher
- Springer Nature
- Number of pages
- 11
- Grant note
- P30CA023168 / Purdue Center for Cancer Research via its NIH NCI R01CA207751; R01CA232589; R21AA026675 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA RSG-CSM130259 / American Cancer Society UAB Breast SPORE Career Development Award
- Language
- English
- Date published
- 01/21/2021
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984459621702771
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