The role of autophagy in the cytotoxicity induced by trastuzumab emtansine (T-DM1) in HER2-positive breast cancer cells

Abstract

Trastuzumab emtansine (T-DM1), an antibody-drug conjugate (ADC) of trastuzumab and cytotoxic agent emtansine (DM1), has been approved for the therapy of metastatic HER2-positive breast cancer after prior treatment of trastuzumab and taxane. The impressive efficacy exhibited by T-DM1 has heightened the need for more further studies on the underlying mechanisms of T-DM1 cytotoxicity. Previous research suggested that autophagy was crucial for cancer therapy, but the role of autophagy in T-DM1 treatment has not been investigated. Here, we demonstrated for the first time that T-DM1 triggered obvious autophagy in HER2-positive SK-BR-3 and BT-474 breast cancer cells. Blocking autophagy with pharmacological inhibitors chloroquine (CQ) or LY294002 partly reduced T-DM1-induced apoptosis and Caspase-3/7 activation, suggesting that autophagy played an essential role in the cytotoxicity induced by T-DM1 in HER2-positive breast cancer cells. Further investigation demonstrated that Akt/mTOR signaling pathway was involved in T-DM1-induced autophagy in a time-dependent manner. Altogether, our results highlighted the important role of autophagy as a novel mechanism for T-DM1-induced cytotoxicity and elucidated the critical relationships between T-DM1-induced autophagy and apoptosis in human HER2-positive breast cancer cells, which provides novel insight into the underlying anti-tumor mechanism of T-DM1.

HER2-Targeted Immunotherapy and Combined Protocols Showed Promising Antiproliferative Effects in Feline Mammary Carcinoma Cell-Based Models

“…In fact, pertuzumab was suggested for the treatment of triple-negative human breast cancer, which express the circular HER2 RNA, encoding for HER2-103, as putatively occurring with the FMCp cell line [ 51 ], which is antagonized by pertuzumab [ 76 ]. Finally, ADC T-DM1 allows a selective delivery of the DM-1 molecule to the HER2-expressing tumor cells, preventing the HER2 homodimerization, and inhibiting the microtubule assembly [ 77 ], which induces cell apoptosis [ 39 , 40 , 77 ], by blocking the AKT/mTOR pathway [ 40 ]. In the experimental assay, T-DM1 was tested in lower concentrations, comparing to mAbs, and showing superior cytotoxic effects, directly dependent on the cell membrane HER2 concentration [ 39 ].…”

“…T-DM1 mechanism is associated to trastuzumab-HER2 conjugation and the release of the DM1 molecule after complex degradation into lysosomes [ 38 ]. The efficacy of this drug depends on the cell membrane HER2 concentration [ 39 ] and allows to decrease the systemic cytotoxic effects of DM1, by its specific delivery to the tumor HER2-overexpression cells [ 38 , 39 ], triggering autophagy and apoptosis [ 40 ]. T-DM1 leads to the inhibition of HER2 ECD shedding and PI3K/AKT pathway, stimulates ADCC, mitotic arrest, and disruption of the intracellular trafficking.…”

The role of ado-trastuzumab emtansine in current clinical practice

“…7 Ado-trastuzumab emtansine retains trastuzumab activity while delivering emtansine to HER2 expressing cells. 4 Upon binding to HER2 receptor, ado-trastuzumab emtansine is internalized and degraded by proteases of acid lysosomes, resulting in release of cytotoxic metabolites into the cell. 4 Emtansine payload binds tubulin disrupting microtubule function, selectively killing HER2-overexpressing cells.…”

“…4 Upon binding to HER2 receptor, ado-trastuzumab emtansine is internalized and degraded by proteases of acid lysosomes, resulting in release of cytotoxic metabolites into the cell. 4 Emtansine payload binds tubulin disrupting microtubule function, selectively killing HER2-overexpressing cells. 7 Additionally, just like trastuzumab, ado-trastuzumab emtansine inhibits HER2 receptor signaling.…”

“…Ado-trastuzumab emtansine is a HER2-targeted antibody-drug conjugate, which binds trastuzumab with microtubule inhibitor, emtansine, via non-cleavable thioether linker. 2,4 Binding of cytotoxic payload to the antibody reduces systemic toxicity by preventing the release of cytotoxic agents into the bloodstream. 5 Trastuzumab is a recombinant monoclonal antibody derived from Chinese hamster ovary cells, while the other components such as emtansine and thioether linker are produced synthetically.…”