TY - JOUR
T1 - Poziotinib Inhibits HER2-Mutant–Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer
AU - Kalra, Rashi
AU - Chen, Ching Hui
AU - Wang, Junkai
AU - Salam, Ahmad Bin
AU - Dobrolecki, Lacey E.
AU - Lewis, Alaina
AU - Sallas, Christina
AU - Yates, Clayton C.
AU - Gutierrez, Carolina
AU - Karanam, Balasubramanyam
AU - Anurag, Meenakshi
AU - Lim, Bora
AU - Ellis, Matthew J.
AU - Kavuri, Shyam M.
N1 - Publisher Copyright:
©2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/8/15
Y1 - 2022/8/15
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-21-3106
DO - 10.1158/0008-5472.CAN-21-3106
M3 - Article
C2 - 35736563
AN - SCOPUS:85136908912
SN - 0008-5472
VL - 82
SP - 2928
EP - 2939
JO - Cancer Research
JF - Cancer Research
IS - 16
ER -