ArticleEBioMedicine2019
Antibody-drug conjugate T-DM1 treatment for HER2+ breast cancer induces ROR1 and confers resistance through activation of Hippo transcriptional coactivator YAP1.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 39 citations in OpenAlex.
- Imaging of ROR1 expression in tumors using radiolabeled affibody molecules.European journal of nuclear medicine and molecular imaging · 2026Article
- Hippo pathway at the crossroads of stemness and therapeutic resistance in breast cancer.Molecular oncology · 2026Review
- ROR1 protein: a pseudokinase at the crossroads of cancer progression and therapy.Molecular biology reports · 2026Review
- Antibody-drug conjugates in breast cancer: mechanisms of resistance and future therapeutic perspectives.NPJ breast cancer · 2025Review
- YAP as a therapeutic target to reverse trastuzumab resistance.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2025Article
- The Role of Receptor Tyrosine Kinase-like Orphan Receptor 1 (ROR1) in Cancer Stem Cell Signaling.International journal of molecular sciences · 2025Review
- Overcoming immunotherapy resistance in bladder cancer with a novel antibody-drug conjugate RC48.Journal for immunotherapy of cancer · 2025Article
- Impact of HER2-targeting antibody drug conjugates in treatment strategies for patients with breast cancer.Heliyon · 2025Review
- Therapeutic challenges in HER2-targeted antibody therapies: trastuzumab and its ADC derivatives in breast cancer.American journal of cancer research · 2025Review
- Mechanisms of resistance to antibody-drug conjugates in cancer therapy: molecular basis and therapeutic strategies.Cancer drug resistance (Alhambra, Calif.) · 2025Review
- Receptor tyrosine kinase-like orphan receptor 1: A novel antitumor target in gastrointestinal cancers.World journal of clinical oncology · 2024Review
- Potential Role of Nrf2, HER2, and ALDH in Cancer Stem Cells: A Narrative Review.The Journal of membrane biology · 2024Review
- Long noncoding RNA DLEU2 and ROR1 pathway induces epithelial-to-mesenchymal transition and cancer stem cells in breast cancer.Cell death discovery · 2024Article
- Therapeutic development targeting host heparan sulfate proteoglycan in SARS-CoV-2 infection.Frontiers in medicine · 2024Review
- Targeted Delivery of Potent Chemical Drugs and RNAi to Drug-Resistant Breast Cancer Using RNA-Nanotechnology and RNA-Ligand Displaying Extracellular vesicles.RNA nanomed · 2024Article
- Review
- A Small Molecule Targeting the Intracellular Tyrosine Kinase Domain of ROR1 (KAN0441571C) Induced Significant Apoptosis of Non-Small Cell Lung Cancer (NSCLC) Cells.Pharmaceutics · 2023Article
- Resistance to antibody-drug conjugates in breast cancer: mechanisms and solutions.Cancer communications (London, England) · 2023Review
- WNT signaling and cancer stemness.Essays in biochemistry · 2022Article
- EGF Receptor Signaling Modulates YAP Activation and Promotes Experimental Proliferative Vitreoretinopathy.Investigative ophthalmology & visual science · 2022Article
Corrections and comments
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Authors and funding
13 authors at 5 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundA 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.
methodsUsing 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.
findingsExposure 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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.