An Acquired HER2T798I Gatekeeper Mutation Induces Resistance to Neratinib in a Patient with HER2 Mutant-Driven Breast Cancer

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 HER2(L869R) but not HER2(L869R/T798I). In contrast, afatinib and the osimertinib metabolite AZ5104 strongly suppressed HER2(L869R/T798I)-induced signaling and cell growth. Acquisition of HER2(T798I) upon development of resistance to neratinib in a breast cancer with an initial activating HER2 mutation suggests HER2(L869R) is a driver mutation. HER2(T798I)-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 HER2(T798I) 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. (C) 2017 AACR.