Open AccessmiR‐221 confers lapatinib resistance by negatively regulating p27 kip1 in HER2‐positive breast cancer
Author(s) -
Huynh Thanh Kieu,
Huang ChihHao,
Chen JhenYu,
Yao JinHan,
Yang YiShiang,
Wei YaLing,
Chen HsiaoFan,
Chen ChiaHung,
Tu ChihYen,
Hsu YuanMan,
Liu LiangChih,
Huang WeiChien
Publication year - 2021
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/cas.15107
Subject(s) - lapatinib , tyrosine kinase inhibitor , downregulation and upregulation , cancer research , epidermal growth factor receptor , tyrosine kinase , dasatinib , proto oncogene tyrosine protein kinase src , breast cancer , protein kinase b , cancer , medicine , trastuzumab , biology , signal transduction , receptor , microbiology and biotechnology , biochemistry , gene
Development of acquired resistance to lapatinib, a dual epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor, severely limits the duration of clinical response in advanced HER2‐driven breast cancer patients. Although the compensatory activation of the PI3K/Akt survival signal has been proposed to cause acquired lapatinib resistance, comprehensive molecular mechanisms remain required to develop more efficient strategies to circumvent this therapeutic difficulty. In this study, we found that suppression of HER2 by lapatinib still led to Akt inactivation and elevation of FOX3a protein levels, but failed to induce the expression of their downstream pro‐apoptotic effector p27 kip1 , a cyclin‐dependent kinase inhibitor. Elevation of miR‐221 was found to contribute to the development of acquired lapatinib resistance by targeting p27 kip1 expression. Furthermore, upregulation of miR‐221 was mediated by the lapatinib‐induced Src family tyrosine kinase and subsequent NF‐κB activation. The reversal of miR‐221 upregulation and p27 kip1 downregulation by a Src inhibitor, dasatinib, can overcome lapatinib resistance. Our study not only identified miRNA‐221 as a pivotal factor conferring the acquired resistance of HER2‐positive breast cancer cells to lapatinib through negatively regulating p27 kip1 expression, but also suggested Src inhibition as a potential strategy to overcome lapatinib resistance.