Trastuzumab emtansine: mechanisms of action and drug resistance

Abstract

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within thetarget cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect ofT-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations ofT-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.

Figure 1

Intracellular trafficking of trastuzumab emtansine (T-DM1). Binding of T-DM1 onto human epidermal growth factor receptor-2 (HER2) on the plasma membrane is followed by entry of the HER2-T-DM1 complex into the cell via receptor-mediated endocytosis. Internalized endocytic vesicles form early endosomes. The load of early endosomes can be recycled back to the cell membrane or the early endosome can mature to a lysosome. Release of DM1 occurs as a result of proteolytic degradation of the antibody part of T-DM1 in the lysosomes. Intracellular lysine (lys)-MCC-DM1 inhibits microtubule assembly, causing mitotic arrest, apoptosis, mitotic catastrophe, and disrupted intracellular trafficking. MCC, non-reducible thioether linker.

Figure 2

Histological findings in a human epidermal growth factor receptor-2-positive, trastuzumab and lapatinib-resistant breast cancer (JIMT-1) xenograft following trastuzumab emtansine treatment. Numerous apoptotic cells are present (stained brown with CytoDeath staining). Hematoxylin counterstain reveals multinucleated giant cells and pathological mitoses (arrows), which are hallmarks of mitotic catastrophe. Mitotic catastrophes were absent in trastuzumab-treated tumors.

Figure 3

Factors influencing the intracellular DM1 level. DM1 may evoke cell death in a concentration-dependent manner, where a threshold concentration of intracellular DM1 and its metabolites needs to be exceeded for cell kill. At high DM1 concentrations mitotic arrest and rapid apoptotic death follow, whereas at lower levels mitotic catastrophe and disrupted intracellular trafficking occur, and at the lowest levels of DM1 cells show resistance. HER2, human epidermal growth factor receptor-2; T-DM1, trastuzumab emtansine.