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An Acquired HER2T798I 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. Cancer Discov; 7(6); 575-85. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.

SUBMITTER: Hanker AB 

PROVIDER: S-EPMC5457707 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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We report a <i>HER2</i><sup>T798I</sup> gatekeeper mutation in a patient with <i>HER2</i><sup>L869R</sup>-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that <i>HER2</i><sup>L869R</sup> is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3<sup>E928G</sup>, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progr  ...[more]

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