Next Article in Journal
Precision Medicine for NSCLC in the Era of Immunotherapy: New Biomarkers to Select the Most Suitable Treatment or the Most Suitable Patient
Next Article in Special Issue
Fighting Drug Resistance through the Targeting of Drug-Tolerant Persister Cells
Previous Article in Journal
Usefulness of Two Independent DNA and RNA Tissue-Based Multiplex Assays for the Routine Care of Advanced NSCLC Patients
Article

Identifying Therapies to Combat Epithelial Mesenchymal Plasticity-Associated Chemoresistance to Conventional Breast Cancer Therapies Using An shRNA Library Screen

1
Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, Brisbane QLD-4102, Australia
2
Translational Research Institute, Brisbane QLD-4102, Australia
3
Invasion and Metastasis Unit, St. Vincent’s Institute, Melbourne VIC 3065, Australia
4
Pharmacogenomics Unit, St. Vincent’s Institute, Melbourne VIC 3065, Australia
5
Institute of Health and Biomedical Innovation, Cancer & Ageing Research Program, Queensland University of Technology, Brisbane 4102, Australia
6
Centre for Tumour and Immune Biology (ZTI), Department of Medicine, Philipps University Marburg, Marburg 35043, Germany
7
Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria 3000, Australia
8
Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria 3010, Australia
9
AID Genomics, Prof. Menahem Plaut 10, Rehovot 7670621, Israel
*
Authors to whom correspondence should be addressed.
Current affiliation: Janssen Cilag Pty Ltd, Pharmaceutical company of Johnson and Johnson, Macquarie Park NSW 2113, Australia.
Current affiliation: Blood Cancer Therapeutics Laboratory, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia.
Cancers 2020, 12(5), 1123; https://doi.org/10.3390/cancers12051123
Received: 30 January 2020 / Revised: 15 April 2020 / Accepted: 21 April 2020 / Published: 30 April 2020
(This article belongs to the Special Issue Cellular Plasticity and the Untapped Therapeutic Potential in Cancer)
Background: Breast cancer (BC) is a heterogeneous disease for which the commonly used chemotherapeutic agents primarily include the anthracyclines (doxorubicin, epirubicin), microtubule inhibitors (paclitaxel, docetaxel, eribulin), and alkylating agents (cyclophosphamide). While these drugs can be highly effective, metastatic tumours are frequently refractory to treatment or become resistant upon tumour relapse. Methods: We undertook a cell polarity/epithelial mesenchymal plasticity (EMP)-enriched short hairpin RNA (shRNA) screen in MDA-MB-468 breast cancer cells to identify factors underpinning heterogeneous responses to three chemotherapeutic agents used clinically in breast cancer: Doxorubicin, docetaxel, and eribulin. shRNA-transduced cells were treated for 6 weeks with the EC10 of each drug, and shRNA representation assessed by deep sequencing. We first identified candidate genes with depleted shRNA, implying that their silencing could promote a response. Using the Broad Institute’s Connectivity Map (CMap), we identified partner inhibitors targeting the identified gene families that may induce cell death in combination with doxorubicin, and tested them with all three drug treatments. Results: In total, 259 shRNAs were depleted with doxorubicin treatment (at p < 0.01), 66 with docetaxel, and 25 with eribulin. Twenty-four depleted hairpins overlapped between doxorubicin and docetaxel, and shRNAs for TGFB2, RUNX1, CCDC80, and HYOU1 were depleted across all the three drug treatments. Inhibitors of MDM/TP53, TGFBR, and FGFR were identified by CMap as the top pharmaceutical perturbagens and we validated the combinatorial benefits of the TGFBR inhibitor (SB525334) and MDM inhibitor (RITA) with doxorubicin treatment, and also observed synergy between the inhibitor SB525334 and eribulin in MDA-MB-468 cells. Conclusions: Taken together, a cell polarity/EMP-enriched shRNA library screen identified relevant gene products that could be targeted alongside current chemotherapeutic agents for the treatment of invasive BC. View Full-Text
Keywords: chemotherapy resistance; combination chemotherapy; doxorubicin; docetaxel; eribulin; TGFBR; FGFR; MDM; TP53; shRNA library screening chemotherapy resistance; combination chemotherapy; doxorubicin; docetaxel; eribulin; TGFBR; FGFR; MDM; TP53; shRNA library screening
Show Figures

Graphical abstract

MDPI and ACS Style

Bhatia, S.; Blick, T.; Pinto, C.; Waltham, M.; Monkman, J.; Ivanova, E.; Pollock, P.M.; Nagaraj, S.H.; Wiegmans, A.P.; Haviv, I.; Simpson, K.J.; Thompson, E.W. Identifying Therapies to Combat Epithelial Mesenchymal Plasticity-Associated Chemoresistance to Conventional Breast Cancer Therapies Using An shRNA Library Screen. Cancers 2020, 12, 1123. https://doi.org/10.3390/cancers12051123

AMA Style

Bhatia S, Blick T, Pinto C, Waltham M, Monkman J, Ivanova E, Pollock PM, Nagaraj SH, Wiegmans AP, Haviv I, Simpson KJ, Thompson EW. Identifying Therapies to Combat Epithelial Mesenchymal Plasticity-Associated Chemoresistance to Conventional Breast Cancer Therapies Using An shRNA Library Screen. Cancers. 2020; 12(5):1123. https://doi.org/10.3390/cancers12051123

Chicago/Turabian Style

Bhatia, Sugandha, Tony Blick, Cletus Pinto, Mark Waltham, James Monkman, Ekaterina Ivanova, Pamela M. Pollock, Shivashankar H. Nagaraj, Adrian P. Wiegmans, Izhak Haviv, Kaylene J. Simpson, and Erik W. Thompson 2020. "Identifying Therapies to Combat Epithelial Mesenchymal Plasticity-Associated Chemoresistance to Conventional Breast Cancer Therapies Using An shRNA Library Screen" Cancers 12, no. 5: 1123. https://doi.org/10.3390/cancers12051123

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop