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 the target 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 of T-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 of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1.

Tumor-linked HER2 expression: association with obesity and lipid-related microenvironment

“…A recent in vivo study (using ApoE −/− and C57BL/6 mice, Table 4 [82], [83], [84], [85], [86], [87], [88], [89]) has recorded the detrimental role of EGFR in the pathogenesis of obesity-related nephropathy [90]. In a clinical study, after analyzing 100 postmenopausal breast cancer specimens, Xuan et al [91] found that tamoxifen resistance was associated with obesity, and EGFR expression was higher in tamoxifen resistance cases compared to tamoxifen sensitive group (Table 5 [ 32], [92], [93], [94]). Overall, the status of EGFR in the lipogenic environment is intricate.…”

“…tumors that express estrogen receptor (ER). It competes with endogenous estrogens to prevent the activation of ERα Trastuzumab [94] Monoclonal antibody inhibitor…”

Tumor Cells Chronically Treated with a Trastuzumab–Maytansinoid Antibody–Drug Conjugate Develop Varied Resistance Mechanisms but Respond to Alternate Treatments

“…One experimental model of ADC resistance was generated by serial exposure of a lung adenocarcinoma xenograft in athymic mice to Vinca-conjugated anti-KS1/4 ADC, and no ABCB1 (MDR1) drug transporter mRNA or protein were observed (15). Tumors inherently refractory to the clinically approved ADC, T-DM1, are reported in both preclinical and clinical settings, although mechanisms of resistance have not been elucidated (16). Phillips and colleagues (17) reported induction of resistance in cultured breast carcinoma cell lines by stepwise exposure to T-DM1.…”

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“…[47] At the time of the primary analysis, median time on study drug was 5. [50] progression-free survival (PFS) of kadcyla or lapatinib plus capecitabine was 9.6 months and 30.9 months. The overall survival (OS) of kadcyla or lapatinib plus capecitabine were 6.4 months and 25.1 months.…”