Therapeutic activity of DCC‐2036, a novel tyrosine kinase inhibitor, against triple‐negative breast cancer patient‐derived xenografts by targeting AXL/MET

Abstract

Triple‐negative breast cancer (TNBC) is insensitive to endocrine therapies and targeted therapies to human epidermal growth factor receptor‐2 (HER2), estrogen receptor (ER) and progesterone receptor (PR). New targets and new targeted therapeutic drugs for TNBC are desperately needed. Our study confirmed that DCC‐2036 inhibited the proliferation, invasion, migration and epithelial‐mesenchymal transition (EMT) of TNBC cells as well as induced apoptosis. Moreover, the antiproliferative activity of DCC‐2036 was more efficient than that of most clinical drugs. In addition, the combination of DCC‐2036 and cisplatin or lapatinib had synergistic effects on TNBC cells. Mechanistically, DCC‐2036 targeted AXL/MET, especially AXL, and regulated the downstream PI3K/Akt‐NFκB signaling to exert its antitumor effect in TNBC. DCC‐2036 also inhibited the growth and metastasis of xenografted MDA‐MB‐231 cells (AXL/MET‐high TNBC cells) but not MDA‐MB‐468 cells (AXL‐low TNBC cells) in NSG mice in vivo. Furthermore, DCC‐2036 significantly inhibited tumor growth and invasion of AXL/MET‐high TNBC PDX tumors but not AXL/MET‐low TNBC PDX tumors. These results highlighted the roles of AXL/MET in cancer growth and metastasis and further verified that the critical targets of DCC‐2036 are AXL and MET, especially AXL. In addition, there was no significant toxicity of DCC‐2036 even at a high dosage. Therefore, DCC‐2036 may be a potential compound to treat TNBC, especially for tumors with AXL/MET overexpression.

Highly‐expressed P2X7 receptor promotes growth and metastasis of human HOS/MNNG osteosarcoma cells via PI3K/Akt/GSK3β/β‐catenin and mTOR/HIF1α/VEGF signaling

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse . Cells undergoing EMT are known to acquire stem cell‐like properties.…”

“…Previous studies indicate that stimulating EMT and increasing CSCs can promote cancer metastasis and relapse. 34,[47][48][49][50] Cells undergoing EMT are known to acquire stem cell-like properties. Loss of epithelial marker E-cadherin, increased expression of mesenchymal markers Fibronectin and Vimentin and the EMT regulator Snail, which are important events in EMT.…”

AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications

“…Rebastinib, designed as a switch-control inhibitor of the BCR-ABL1 tyrosine kinase [244], also has striking activity against AXL in TNBC cells [245]. It is now in phase I/II clinical trials for the treatment of locally advanced or metastatic solid tumours, CML and breast cancer (NCT03717415, NCT03601897, NCT00827138, and NCT02824575).…”

The Role of the Receptor Tyrosine Kinase Axl in Carcinogenesis and Development of Therapeutic Resistance: An Overview of Molecular Mechanisms and Future Applications

“…This diversification of signalling pathways is ligand-independent and is triggered by the association of Axl with EGFR, c-Met, and PDGFR [31]. The TKI DCC-2036 suppresses Axl/c-Met-PI3K/AKT-NF-κB signalling to decrease growth and metastasis in a TNBC xenografted model overexpressing Axl [104].…”