Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugated to the microtubule-targeting agent emtansine (DM1). T-DM1 is an effective agent in the treatment of patients with HER2-positive breast cancer whose disease has progressed on the first-line trastuzumab containing chemotherapy. However, both primary and acquired tumour resistance limit its efficacy. Increased levels of the phosphorylated form of Translationally Controlled Tumour Protein (phospho-TCTP) have been shown to be associated with a poor clinical response to trastuzumab therapy in HER2-positive breast cancer. Here we show that phospho-TCTP is essential for correct mitosis in human mammary epithelial cells. Reduction of phospho-TCTP levels by dihydroartemisinin (DHA) causes mitotic aberration and increases microtubule density in the trastuzumab-resistant breast cancer cells HCC1954 and HCC1569. Combinatorial studies show that T-DM1 when combined with DHA is more effective in killing breast cells compared to the effect induced by any single agent. In an orthotopic breast cancer xenograft model (HCC1954), the growth of the tumour cells resumes after having achieved a complete response to T-DM1 treatment. Conversely, DHA and T-DM1 treatment induces a severe and irreversible cytotoxic effect, even after treatment interruption, thus, improving the long-term efficacy of T-DM1. These results suggest that DHA increases the effect of T-DM1 as poison for microtubules and supports the clinical development of the combination of DHA and T-DM1 for the treatment of aggressive HER2-overexpressing breast cancer.

D'Amico, S., Krasnowska, E.k., Manni, I., Toietta, G., Baldari, S., Piaggio, G., et al. (2020). DHA Affects Microtubule Dynamics Through Reduction of Phospho-TCTP Levels and Enhances the Antiproliferative Effect of T-DM1 in Trastuzumab-Resistant HER2-Positive Breast Cancer Cell Lines. CELLS, 9(5), 1260 [10.3390/cells9051260].

DHA Affects Microtubule Dynamics Through Reduction of Phospho-TCTP Levels and Enhances the Antiproliferative Effect of T-DM1 in Trastuzumab-Resistant HER2-Positive Breast Cancer Cell Lines

Ranalli M.;Gambacurta A.;Bernassola F.;
2020

Abstract

Trastuzumab emtansine (T-DM1) is an anti-human epidermal growth factor receptor 2 (HER2) antibody-drug conjugated to the microtubule-targeting agent emtansine (DM1). T-DM1 is an effective agent in the treatment of patients with HER2-positive breast cancer whose disease has progressed on the first-line trastuzumab containing chemotherapy. However, both primary and acquired tumour resistance limit its efficacy. Increased levels of the phosphorylated form of Translationally Controlled Tumour Protein (phospho-TCTP) have been shown to be associated with a poor clinical response to trastuzumab therapy in HER2-positive breast cancer. Here we show that phospho-TCTP is essential for correct mitosis in human mammary epithelial cells. Reduction of phospho-TCTP levels by dihydroartemisinin (DHA) causes mitotic aberration and increases microtubule density in the trastuzumab-resistant breast cancer cells HCC1954 and HCC1569. Combinatorial studies show that T-DM1 when combined with DHA is more effective in killing breast cells compared to the effect induced by any single agent. In an orthotopic breast cancer xenograft model (HCC1954), the growth of the tumour cells resumes after having achieved a complete response to T-DM1 treatment. Conversely, DHA and T-DM1 treatment induces a severe and irreversible cytotoxic effect, even after treatment interruption, thus, improving the long-term efficacy of T-DM1. These results suggest that DHA increases the effect of T-DM1 as poison for microtubules and supports the clinical development of the combination of DHA and T-DM1 for the treatment of aggressive HER2-overexpressing breast cancer.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/11
English
phospho-TCTP
DHA
T-DM1
HER2-positive breast cancer
Animals
Apoptosis
Artemisinins
Biomarkers, Tumor
Breast Neoplasms
Cell Line, Tumor
Cell Proliferation
DNA Damage
Female
Humans
Mice, SCID
Microtubules
Mitosis
Oxidative Stress
Phosphatidylinositol 3-Kinases
Phosphorylation
Proto-Oncogene Proteins c-akt
Reactive Oxygen Species
Receptor, ErbB-2
Signal Transduction
Trastuzumab
Tumor Protein, Translationally-Controlled 1
Drug Resistance, Neoplasm
D'Amico, S., Krasnowska, E.k., Manni, I., Toietta, G., Baldari, S., Piaggio, G., et al. (2020). DHA Affects Microtubule Dynamics Through Reduction of Phospho-TCTP Levels and Enhances the Antiproliferative Effect of T-DM1 in Trastuzumab-Resistant HER2-Positive Breast Cancer Cell Lines. CELLS, 9(5), 1260 [10.3390/cells9051260].
D'Amico, S; Krasnowska, Ek; Manni, I; Toietta, G; Baldari, S; Piaggio, G; Ranalli, M; Gambacurta, A; Vernieri, C; Di Giacinto, F; Bernassola, F; de Braud, F; Lucibello, M
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/289375
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