An Acquired HER2^T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer.

ABSTRACT: We report a HER2^T798I gatekeeper mutation in a patient with HER2^L869R-mutant breast cancer with acquired resistance to neratinib. Laboratory studies suggested that HER2^L869R is a neratinib-sensitive, gain-of-function mutation that upon dimerization with mutant HER3^E928G, also present in the breast cancer, amplifies HER2 signaling. The patient was treated with neratinib and exhibited a sustained partial response. Upon clinical progression, HER2^T798I was detected in plasma tumor cell-free DNA. Structural modeling of this acquired mutation suggested that the increased bulk of isoleucine in HER2^T798I reduces neratinib binding. Neratinib blocked HER2-mediated signaling and growth in cells expressing HE

SUBMITTER: Hanker AB 

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

REPOSITORIES: biostudies-literature