AXL knockdown gene signature reveals a drug repurposing opportunity for a class of antipsychotics to reduce growth and metastasis of triple-negative breast cancer

Abstract

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.

Antipsychotic Drug Trifluoperazine Suppresses Colorectal Cancer by Inducing G0/G1 Arrest and Apoptosis

“…TFP treatment induced apoptosis of cancer cells in lots of studies (Park et al, 2016; Jiang et al, 2017; Feng et al, 2018; Goyette et al, 2019). Deregulation of cell death is involved in the pathogenesis of cancer (Qi et al, 2018).…”

“…It could overcome EGFR inhibitor and chemotherapy resistance of lung cancer by targeting cancer stem-like cells. It also showed efficacies in suppressing metastasis in several cancers (Ashleigh et al, 2015; Feng et al, 2018; Liu et al, 2018; Goyette et al, 2019). TFP induced apoptosis of cancer cells and disrupting cell cycle progression in vitro and in vivo in numerous models.…”

“…In hepatocellular carcinoma, TFP could activate forkhead box O1 (FOXO1)–related signals to inhibit tumor growth (Jiang et al, 2017). The receptor tyrosine kinase AXL is another target of TFP to reduce growth and metastasis of breast cancer (Goyette et al, 2019). Immune-based cancer therapy is a promising strategy to treat cancer.…”

In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review

“…Goyette et al (2019) showed that FLU affects proliferation, migration and invasion of MDA-MB-231 and Hs578T human breast cancer cells. The drug at a concentration of 20 μM reduced invasion by about 75% and 40%, while the migration was reduced to less than 0.5 and 0.4 μm/min, respectively for MDA-MB-231 and Hs578T cells.Moreover, a dose-dependent reduction in the proliferation of human breast cancer cells expressed by luciferase (MDA-MB-231-Luc) was observed.…”

AXL as a Target in Breast Cancer Therapy

“…Indeed, a role for AXL in the progression of various breast cancer subtypes has been identified. ese include in inflammatory breast cancer [35], TNBC [64], and ER-positive [54], as well as HER2-amplified [4] breast cancers. AXL has also been implicated in more rare forms of breast tumors, including in phyllodes tumors of the breast, which are tumors that originate in stromal tissue [65], as well as in male breast cancer [66].…”