Inhibitory effect of the novel tyrosine kinase inhibitor DCC-2036 on triple-negative breast cancer stem cells through AXL-KLF5 positive feedback loop

Abstract

Triple-negative breast cancer (TNBC), an aggressive histological subtype of breast cancer, exhibits a high risk of early recurrence rate and a poor prognosis, and it is primarily associated with the abundance of cancer stem cells (CSCs). At present, the strategies for effectively eradicating or inhibiting TNBC CSCs are still limited, which makes the development of novel drugs with anti-CSCs function be of great value for the treatment of TNBC, especially the refractory TNBC. In this study, we found that the small-molecule tyrosine kinase inhibitor DCC-2036 suppressed TNBC stem cells by inhibiting the tyrosine kinase AXL and the transcription factor KLF5. DCC-2036 downregulated the expression of KLF5 by decreasing the protein stability of KLF5 via the AXL-Akt-GSK3β signal axis, and in turn, the downregulation of KLF5 further reduced the expression of AXL via binding to its promotor (−171 to −162 bp). In addition, p-AXL/AXL levels were positively correlated with KLF5 expression in human TNBC specimens. These findings indicated that DCC-2036 is able to suppress the CSCs in TNBC by targeting the AXL-KLF5 positive feedback loop. Moreover, our findings indicated that DCC-2036 increased the sensitivity of TNBC chemotherapy. Therefore, this study proposes a potential drug candidate and several targets for the treatment of refractory TNBC.

UCHL1 contributes to insensitivity to endocrine therapy in triple-negative breast cancer by deubiquitinating and stabilizing KLF5

“…It activates the expression of NANOG and FGFBP1 in TNBC, which are required for the maintenance of the cancer stem cell (CSC) population [ 28 , 38 ]. Pharmaceutical inhibition of KLF5 could significantly suppress the CSC properties of TNBC and enhance chemotherapy responses [ 39 , 40 ]. KLF5 can directly bind to the 5’ regulatory region of EGFR and enhance its transcription [ 33 ].…”

Basal‐like mammary carcinomas stimulate cancer stem cell properties through AXL‐signaling to induce chemotherapy resistance

“…Through its capacity to stimulate oncogenic PI3K‐AKT‐mTOR, MAPK, JAK‐STAT and SRC‐FAK signaling, AXL can sustain aberrant stem cell renewal, epithelial‐to‐mesenchymal transition (EMT), immune evasion and cancer cell invasion 48,49 . Particularly in normal and tumor cells of the mammary gland, AXL was frequently shown to play a critical role in the maintenance of stem cell properties 48,50‐52 . Inline, several reports suggested an implication of the AXL signaling in drug‐resistant phenotypes of TNBC.…”

“…48,49 Particularly in normal and tumor cells of the mammary gland, AXL was frequently shown to play a critical role in the maintenance of stem cell properties. 48,[50][51][52] Inline, several reports suggested an implication of the AXL signaling in drug-resistant phenotypes of TNBC. Wilson et al identified R428 synergizing with antimitotic agents in resistant cell lines.…”