Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

Abstract

Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance. HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human-positive breast cancer explants. We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells. knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation. Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer. .

Anti‑proliferative and pro‑apoptotic effects of rosemary and constituent terpenoids in a model for the HER‑2‑enriched molecular subtype of clinical breast cancer

“…In the colorectal adenocarcinoma-derived Caco-2 cell line, CSOL and CA induce G 2 /M phase arrest via distinct modulation of increased cyclin B1 or decreased cyclin A levels (28). Furthermore, treatment of HER-2-expressing breast cancer cells with trastuzumab-emtansine (T-DM1) conjugate upregulates cyclin B1 expression in T-DM1-sensitive, but not resistant, phenotypes (29); thus, high levels of cyclin B1 in G 2 /M arrested cells raise the possibility that proteasome-mediated degradation of the G 2 -specific cyclin may be impaired resultant to treatment with CA and CSOL. Furthermore, CA has been documented to synergize the antitumor activity of trastuzumab in HER-2-positive breast cancer cells (30), and CSOL has been identified to function as a potent inhibitor of transcriptional activation of inducible COX-2 and of prostaglandin production in 184-B5/HER cells.…”

Crosstalk between HER2 and PD-1/PD-L1 in Breast Cancer: From Clinical Applications to Mathematical Models

“…In short, trastuzumab resistance is mediated by (1) impaired interaction of trastuzumab to HER2 (via MUC4, p95HER2, CDK2), (2) an altered or parallel intracellular PI3K/AKT/mTOR signaling pathway, (3) mutation of PIK3CA gene, and (4) higher levels of cyclin-E, fatty acid synthase (FASN), and/or NmU. Similarly, potential reasons for T-DM1 resistance include difficulties in binding with the receptor (due to MUC4, p95HER2), impaired receptor internalization, improper release of cytotoxic agent, and/or activation of parallel pathways [85,86]. All of the FDA-approved anti-HER2 drugs are associated with resistance development via one or more of the above-listed pathways.…”

Identification of Potential Target Genes in HER-2 Positive Breast Cancer by Bioinformatics Analysis.

“…CCNB1, known as cyclin B1, is a highly conserved cyclin. Testing cyclin B1 in patients treated with T-DM1 was beni cal to identify early the patients more likely to bene t from this drug [38]. CENPF is a cell cycle-regulated protein associated with kinetochores, and is overexpressed in breast cancer, hepatocellular carcinoma and other tumors [39][40].…”