AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple negative breast cancer
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Marie-Anne Goyette1,2, Rebecca Cusseddu1,2, Islam Elkholi1,2, Afnan Abu-Thuraia1,2, Nehme El-Hachem1, Benjamin Haibe-Kains3,4,5,6,7, Jean-Philippe Gratton8 and Jean-François Côté1,2,9,10
1 Montreal Clinical Research Institute (IRCM), Montréal, QC, H2W 1R7, Canada
2 Molecular Biology Programs, Université de Montréal, Montréal, QC, H3T 1J4, Canada
3 Princess Margaret Cancer Centre, Toronto, University Health Network, ON M5G 1L7, Canada
4 Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
5 Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada
6 Ontario Institute for Cancer Research, Toronto, ON M5G 1L7, Canada
7 Vector Institute, Toronto, ON M5G 1L7, Canada
8 Department of Pharmacology and Physiology, Université de Montréal, Montréal, QC, H3C 3J7, Canada
9 Department of Biochemistry and Molecular Medicine, Université de Montréal, Montréal, QC, H3C 3J7, Canada
10 Department of Anatomy and Cell Biology, McGill University, Montréal, QC, H3A 0C7, Canada
|Jean-François Côté,||email:||[email protected]|
Keywords: triple-negative breast cancer; drug repurposing; AXL; phenothiazines; metastasis
Received: October 03, 2018 Accepted: February 15, 2019 Published: March 12, 2019
Triple-Negative Breast Cancer (TNBC) is an aggressive cancer subtype that is associated with a poor prognosis due to its propensity to form metastases. The receptor tyrosine kinase AXL plays a role in tumor cell dissemination and its expression in breast cancers correlates with poor patient survival. Here, we explored whether already used drugs might elicit a gene signature similar to that seen with AXL knockdown in TNBC cells and which could, therefore, offer an opportunity for drug repurposing. To this end, we queried the Connectivity Map with an AXL gene signature which revealed a class of dopamine receptors antagonists named phenothiazines (Thioridazine, Fluphenazine and Trifluoperazine) typically used as anti-psychotics. We next tested if these drugs, similarly to AXL depletion, were able to limit growth and metastatic progression of TNBC cells and found that phenothiazines are able to reduce cell invasion, proliferation, viability and increase apoptosis of TNBC cells in vitro. Mechanistically, these drugs did not affect AXL activity but instead reduced PI3K/AKT/mTOR and ERK signaling. When administered to mice bearing TNBC xenografts, phenothiazines were able to reduce tumor growth and metastatic burden. Collectively, these results suggest that these antipsychotics display anti-tumor and anti-metastatic activity and that they could potentially be repurposed, in combination with standard chemotherapy, for the treatment of TNBC.
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