Home Blog of Signal Transduction Autophagy Ferroptosis MiR-221 confers lapatinib resistance by negatively regulating p27 kip1 in HER2-positive breast cancer

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

MiR-221 confers lapatinib resistance by negatively regulating p27 kip1 in HER2-positive breast cancer

Development of acquired resistance to lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, severely limited the duration of clinical response in advanced HER2-driven breast cancer patients. Although the compensatory activation of PI3K/Akt survival signal has been proposed to cause the acquired lapatinib resistance; however, the 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 the Akt inactivation and elevation of FOX3a protein level but failed to induce the expression of their downstream pro-apoptotic effector p27kip1 , a cyclin-dependent kinase inhibitor. The elevation of miR-221 was found to contribute to the development of the acquired lapatinib resistance by targeting p27kip1 expression. Furthermore, the upregulation of miR-221 was mediated by the lapatinib-induced Src family tyrosine kinase and subsequent NF-kB activations. The reversal of miR-221 upregulation and p27kip1 downregulation by 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 p27kip1 expression but also suggested Src inhibition as a potential strategy to overcome lapatinib resistance.

Related Products

Cat.No. Product Name Information
S2111 Lapatinib Lapatinib, used in the form of Lapatinib Ditosylate, is a potent EGFR and ErbB2 inhibitor with IC50 of 10.8 and 9.2 nM in cell-free assays, respectively. Lapatinib induces ferroptosis and autophagic cell death.

Related Targets

Ferroptosis HER2 Autophagy EGFR