An acquired HER2(T798I) gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer Journal Article
| Authors: | 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. Jr; Lalani, A. S.; Cross, D.; Lovly, C. M.; Meiler, J.; Arteaga, C. L. |
| Article Title: | An acquired HER2(T798I) gatekeeper mutation induces resistance to neratinib in a patient with HER2 mutant-driven breast cancer |
| 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. © 2017 AACR. |
| Journal Title: | Cancer Discovery |
| Volume: | 7 |
| Issue: | 6 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-06-01 |
| Start Page: | 575 |
| End Page: | 585 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-16-1431 |
| PROVIDER: | scopus |
| PMCID: | PMC5457707 |
| PUBMED: | 28274957 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 July 2017 -- Source: Scopus |
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