An acquired HER2T798I gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer

Ariella B. Hanker, Monica Red Brewer, Jonathan H. Sheehan, James P. Koch, Gregory R. Sliwoski, Rebecca Nagy, Richard Lanman, Michael F. Berger, David M. Hyman, David B. Solit, Jie He, Vincent Miller, Richard E. Cutler, Alshad S. Lalani, Darren Cross, Christine M. Lovly, Jens Meiler, Carlos L. Arteaga

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Abstract

We report a HER2T798I gatekeeper mutation in a patient with HER2L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HER2L869R but not HER2L869R/T798I. In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2L869R/T798I-induced signaling and cell growth. Acquisition of HER2T798I upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2L869R is a driver mutation. HER2T798I-mediated neratinib resistance may be overcome by other irreversible HER2 inhibitors like afatinib. SIGNIFICANCE: We found an acquired HER2 gatekeeper mutation in a patient with HER2-mutant breast cancer upon clinical progression on neratinib. We speculate that HER2T798I may arise as a secondary mutation following response to effective HER2 tyrosine kinase inhibitors (TKI) in other cancers with HER2-activating mutations. This resistance may be overcome by other irreversible HER2 TKIs, such as afatinib.

Original languageEnglish (US)
Pages (from-to)575-585
Number of pages11
JournalCancer Discovery
Volume7
Issue number6
DOIs
StatePublished - Jan 1 2017

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ASJC Scopus subject areas

  • Oncology

Cite this

Hanker, A. B., Brewer, M. R., Sheehan, J. H., Koch, J. P., Sliwoski, G. R., Nagy, R., Lanman, R., Berger, M. F., Hyman, D. M., Solit, D. B., He, J., Miller, V., Cutler, R. E., Lalani, A. S., Cross, D., Lovly, C. M., Meiler, J., & Arteaga, C. L. (2017). An acquired HER2T798I gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer. Cancer Discovery, 7(6), 575-585. https://doi.org/10.1158/2159-8290.CD-16-1431