Poziotinib Inhibits HER2-Mutant-Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer

Authors

Rashi Kalra
Ching Hui Chen
Junkai Wang
Ahmad Bin Salam
Lacey E Dobrolecki
Alaina Lewis
Christina Sallas
Clayton C Yates
Carolina Gutierrez
Balasubramanyam Karanam
Meenakshi Anurag
Bora Lim
Matthew J Ellis
Shyam M Kavuri

Publication Date

8-16-2022

Journal

Cancer Research

Abstract

UNLABELLED: The pan-HER tyrosine kinase inhibitor (TKI) neratinib is therapeutically active against metastatic breast cancers harboring activating HER2 mutations, but responses are variable and often not durable. Here we demonstrate that recurrent HER2 mutations have differential effects on endocrine therapy responsiveness, metastasis, and pan-HER TKI therapeutic sensitivity. The prevalence and prognostic significance may also depend on whether the HER2 mutant has arisen in the context of lobular versus ductal histology. The most highly recurrent HER2 mutant, L755S, was particularly resistant to neratinib but sensitive to the pan-HER TKI poziotinib, alone or in combination with fulvestrant. Poziotinib reduced tumor growth, diminished multiorgan metastasis, and inhibited mTOR activation more effectively than neratinib. Similar therapeutic effects of poziotinib were observed in both an engineered HER2L755S MCF7 model and a patient-derived xenograft harboring a HER2G778_P780dup mutation. Overall, these findings support the need for clinical evaluation of poziotinib for the treatment of HER2-mutant metastatic breast cancer.

SIGNIFICANCE: Evaluation of the functional impact of HER2 mutations on therapy-induced resistance and metastasis identifies robust antitumor activity of poziotinib and supports the clinical evaluation of poziotinib in ER+ HER2 mutant breast cancer.

Keywords

Breast Neoplasms, Drug Resistance, Neoplasm, Female, Humans, Protein Kinase Inhibitors, Quinazolines, Quinolines, Receptor, ErbB-2

Comments

Supplementary Materials

PMID: 35736563