Dataset Information

Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab.

ABSTRACT: Background:The aberrant expression of HER2 is highly associated with tumour occurrence and metastasis, therefore HER2 is extensively targeted for tumour immunotherapy. For example, trastuzumab and pertuzumab are FDA-approved monoclonal antibodies that target HER2-positive tumour cells. Despite their advances in clinical applications, emerging resistance to these two HER2-targeting antibodies has hindered their further application. Somatic mutations in HER2 receptor have been identified as one of the major reasons for resistance to anti-HER2 antibodies. Methods:We analysed the frequency of somatic mutations in various tumour types based on TCGA and COSMIC databases. Then, the effect of the most frequent mutation (S310F) on the interaction between pertuzumab and HER2 was analysed by molecular modelling analysis. The effect of the S310F mutation was further evaluated through multiple in vitro binding experiments and antitumour activity assays. Results:We found through bioinformatics analysis that S310F, an activating mutation in the HER2 extracellular domain, was the most frequent mutation in HER2. The S310F mutation was shown to confer resistance of HER2-positive tumour cells to pertuzumab treatment. With molecular modelling analysis, we confirmed the possibility that the S310F mutation might disrupt the interaction between pertuzumab and HER2 as a result of a significant change in the critical residue S310. Further functional analyses revealed that the S310F mutation completely abolished pertuzumab binding to HER2 receptor and inhibited pertuzumab antitumour efficacy. Conclusion:We demonstrated the loss-of-function mechanism underlying pertuzumab resistance in HER2-positive tumour cells bearing the S310F mutation.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC6941612 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab.

Zhang Ying Y Wu Shanshan S Zhuang Xinlei X Weng Gaoqi G Fan Jiansheng J Yang Xiaoyue X Xu Yingchun Y Pan Liqiang L Hou Tingjun T Zhou Zhan Z Chen Shuqing S

OncoTargets and therapy 20191230

<h4>Background</h4>The aberrant expression of HER2 is highly associated with tumour occurrence and metastasis, therefore HER2 is extensively targeted for tumour immunotherapy. For example, trastuzumab and pertuzumab are FDA-approved monoclonal antibodies that target HER2-positive tumour cells. Despite their advances in clinical applications, emerging resistance to these two HER2-targeting antibodies has hindered their further application. Somatic mutations in HER2 receptor have been identified a ...[more]

PMID: 31920346

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Project description:BackgroundCabozantinib, a tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 (FLT3), MET, AXL, vascular endothelial growth factor receptor, and KIT, is approved for use in multiple malignancies. We assessed the safety and tolerability of cabozantinib in AML, given up-regulation of multiple relevant pathways.MethodsAdults were eligible if they were 18 years old or older with relapsed/refractory AML or if they were 70 years old or older with newly diagnosed AML but were ineligible for conventional therapy. Cabozantinib was administered in 28-day cycles, and dose escalation occurred via cohorts. A pharmacodynamic evaluation of serial plasma samples via a plasma inhibitory assay (PIA) was used to assess FLT3-inhibitory activity in FLT3-mutant cell lines.ResultsAmong 18 patients enrolled, 5 were found to harbor FLT3/ITD mutations. Sixteen patients (89%) had relapsed/refractory AML, and most were treated with 2 or more lines of prior treatment. No dose-limiting toxicities (DLTs) were detected at the first dose level (40 mg daily), but 2 patients experienced DLTs at the next level (60 mg daily). The remaining patients were then dosed at 40 mg daily, the maximum tolerated dose (MTD). Additional grade 2 or higher toxicities, possibly/probably related to cabozantinib, included fatigue, nausea, transaminitis, and electrolyte imbalance. No patients had a marrow response according to formal criteria, but 4 had peripheral blast reductions; 2 of these 4 patients transiently cleared circulating blasts. One patient experienced a reduction in marrow blasts, and 1 had stable disease. The FLT3-inhibitory activity of plasma samples, as assessed with the PIA, revealed potent and sustained inhibition in FLT3/ITD and, notably, F691 tyrosine kinase domain (TKD)-mutant cells.ConclusionsCabozantinib is well tolerated in AML patients at an MTD of 40 mg daily and is a potent inhibitor of FLT3/ITD- and F691 TKD-altered tyrosine kinases. Cancer 2018;124:306-14. © 2017 American Cancer Society.

Dataset Information

Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab.

Publications

Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab.

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