Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells.

Guangmin Li,Daniela Bumbaca Yadav,Mark X Sliwkowski,Ben-Quan Shen,Gail D Lewis Phillips,Jun Guo,Jennifer A Lacap,Lisa M Crocker

doi:10.1158/1535-7163.mct-17-0296

Abstract

The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and upregulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1-resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1-resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Mol Cancer Ther; 17(7); 1441-53. ©2018 AACR.

Highlights

The HER2/erbB2 oncogene encodes a 185-kDa transmembrane receptor tyrosine kinase (RTK) that belongs to the EGFR family and regulates proliferation, differentiation, apoptosis, and metastasis [1]
KPL-4 parental cells are insensitive to trastuzumab, which was maintained in KPL-4 TR cells (Fig. 1A)
We observed that T-DM1–resistant BT-474M1 cells manifested resistance to trastuzumab, compared with parental cells (Fig. 1C)

Summary

Introduction

The HER2/erbB2 oncogene encodes a 185-kDa transmembrane receptor tyrosine kinase (RTK) that belongs to the EGFR family and regulates proliferation, differentiation, apoptosis, and metastasis [1]. Trastuzumab (Herceptin), a humanized antibody directed against the HER2 extracellular domain [3], is approved for treating HER2-positive breast cancer in the metastatic [4] and adjuvant settings [5]. Mechanisms attributed to trastuzumab activity include inhibition of HER2/HER3/PI3K signaling [6, 7], prevention of HER2 ectodomain shedding [8], initiation of G1 arrest via induction of the cyclin-dependent kinase inhibitor p27KIP1 [9], and inhibition of angiogenesis [10]. Trastuzumab engages Fc receptor-expressing immune effector cells to induce antibody-dependent, cell-mediated cytotoxicity A proportion of patients do not respond to trastuzumab because of de novo or acquired resistance Trastuzumab engages Fc receptor-expressing immune effector cells to induce antibody-dependent, cell-mediated cytotoxicity (ADCC; ref. 9).

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