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EBioMedicine. 2019 May 10. pii: S2352-3964(19)30300-7. doi: 10.1016/j.ebiom.2019.04.061. [Epub ahead of print]

Antibody-drug conjugate T-DM1 treatment for HER2+ breast cancer induces ROR1 and confers resistance through activation of Hippo transcriptional coactivator YAP1.

Author information

1
Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada; Park View Specialized Hospital, Chittagong, Bangladesh. Electronic address: sislam83@kfshrc.edu.sa.
2
Mohammed Bin Rashid University of Medicine and Health Sciences, College of Medicine, Dubai, United Arab Emirates; The Centre for Applied Genomics, Department of Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
3
Biochemistry and Molecular Biology, University of Chittagong, Chittagong, Bangladesh.
4
Neurogen Technologies Ltd, Genetics and Genome Biology Department, Dhaka, Bangladesh.
5
Holy Family Red Crescent Medical College, Dhaka, Bangladesh.
6
Department of Pharmacy, Noakhali Science and Technology University, Noakhali, Bangladesh.
7
Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
8
Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Abstract

BACKGROUND:

A newly developed drug trastuzumab emtansine (T-DM1) has improved the survival of breast cancer (BC) patients. Despite an impressive initial clinical response, a subgroup of patient develop resistance and present therapeutic challenges. The underlying resistance mechanisms are not fully investigated. We report that T-DM1 treatment modulates the expression of ROR1 (type 1 receptor tyrosine kinase-like orphan receptor) and induces self-renewal of cancer stem cells (CSCs) leading to therapeutic resistance.

METHODS:

Using BC patient tumor samples, and BC cell lines we gained insight into the T-DM1 treatment induced ROR1 overexpression and resistance. In vitro sphere forming assays and in vivo extreme dilution assays were employed to analyze the stemness and self-renewal capacity of the cells. A series of molecular expression and protein assays including qRT-PCR, FACS-sorting, ELISA, immunostaining, Western blotting were used to provide evidence.

FINDINGS:

Exposure of cells to T-DM1 shifted ROR1 expression from low to high, enriched within the CSC subpopulation, coincident with increased Bmi1 and stemness factors. T-DM1 induced ROR1 cells showed high spheroid and tumor forming efficiency in vitro and in an animal model exhibiting shorter tumor-free time. Mechanistically, the overexpression of ROR1 is partly induced by the activation of YAP1 and its target genes. Silencing of ROR1 and YAP1 by pharmacologic inhibitors and/or sh/siRNA inhibited spheroid formation, the initiation of tumors and the capacity for self-renewal and ROR1 overexpression.

INTERPRETATIONS:

The results presented here indicate that simultaneous targeting of ROR1 and YAP1 may suppress CSC self-renewal efficacy and inhibit tumor progression in BC. In this manner such treatments may overcome the T-DM1 mediated therapeutic resistance and improve clinical outcome. FUND: This study was supported by Neurogen Technologies for interdisciplinary research.

PMID:
31085100
DOI:
10.1016/j.ebiom.2019.04.061
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