Dasatinib sensitises triple negative breast cancer cells to chemotherapy by targeting breast cancer stem cells

Abstract

BackgroundPatients with triple negative breast cancer (TNBC) exhibit poor prognosis and are at high risk of tumour relapse, due to the resistance to chemotherapy. These aggressive phenotypes are in part attributed to the presence of breast cancer stem cells (BCSCs). Therefore, targeting BCSCs is a priority to overcoming chemotherapy failure in TNBCs.MethodsWe generated paclitaxel (pac)-resistant TNBC cells which displayed higher sphere forming potential and percentage of BCSC subpopulations compared to the parental cells. A screen with various kinase inhibitors revealed dasatinib, a Src kinase family inhibitor, as a potent suppressor of BCSC expansion/sphere formation in pac-resistant TNBC cells.ResultsWe found dasatinib to block pac-induced BCSC enrichment and Src activation in both parental and pac-resistant TNBC cells. Interestingly, dasatinib induced an epithelial differentiation of the pac-resistant mesenchymal cells, resulting in their enhanced sensitivity to paclitaxel. The combination treatment of dasatinib and paclitaxel not only decreased the BCSCs numbers and their sphere forming capacity but also synergistically reduced cell viability of pac-resistant cells. Preclinical models of breast cancer further demonstrated the efficiency of the dasatinib/paclitaxel combination treatment in inhibiting tumour growth.ConclusionsDasatinib is a promising anti-BCSC drug that could be used in combination with paclitaxel to overcome chemoresistance in TNBC.

Retracted: Long noncoding RNA MALAT1 promotes the stemness of esophageal squamous cell carcinoma by enhancing YAP transcriptional activity

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The tumor promoting roles of long noncoding RNA (lncRNA) MALAT1 have been revealed in various cancers; however, its roles in esophageal squamous cell carcinoma (ESCC) have not previously been disclosed. A lot of work has attempted to identify potential CSC-targeting drugs.For example, recent work has disclosed that dasatinib enhances the chemotherapeutic sensitivity of triple negative breast cancer (TNBC) cells by targeting breast CSCs and could be used in combination with paclitaxel to overcome chemoresistance in TNBC [3]. In addition, knockdown of MALAT1 attenuated the stemness of ESCC cells, as evidenced by a decrease in spheroid formation capacity, stemness marker expression and aldehyde dehydrogenase 1 activity.

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“…Therefore, it is essential to find novel targets which could facilitate the development of the treatment of ESCC.Cancer stem cells (CSCs), also called tumor initiating cells, are regarded as the origin of cancer development and progression. A lot of work has attempted to identify potential CSC-targeting drugs.For example, recent work has disclosed that dasatinib enhances the chemotherapeutic sensitivity of triple negative breast cancer (TNBC) cells by targeting breast CSCs and could be used in combination with paclitaxel to overcome chemoresistance in TNBC [3]. Venetoclax disrupts the energy metabolism of leukemia stem cells with azacitidine in patients with acute myeloid leukemia [4].…”

Targeting SRC Kinase Signaling in Pancreatic Cancer Stem Cells

“…In this context, it has been recently shown that SRC functionality is relevant for MCF7 breast CSC proliferation and self-renewal by, at least in part, regulation of CSC glucose metabolism [ 75 ]. Thus, while SRC has been well explored and its role characterized in CSCs of other tumor entities [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ], little is known regarding the role of SRC in PaCSCs and whether targeting SRC kinases in PaCSCs is therapeutically relevant.…”

“…The overexpression, activation, or deregulation of SRC and other family members of the SFKs has been associated with different solid tumors (reviewed by Martellucci et al in [ 37 ]), including, for example, ovarian cancer [ 39 , 40 ] and breast cancer [ 41 , 42 , 43 ]. At the level of CSCs, SRC has also been linked to several key CSC-associated pathways or phenotypes, such as EMT, pluripotency, self-renewal, and metastasis [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ], but, as mentioned above, the role of SRC kinases in PaCSCs has been underexplored. Thus, in this study, we sought to determine whether SRC -kinases are biologically important for PaCSCs using primary PDAC cultures established from patient-derived xenografts (PDXs) that we have previously shown to contain PaCSCs [ 25 ].…”

The GEF‐H1/PKD3 signaling pathway promotes the maintenance of triple‐negative breast cancer stem cells

“…TNBC patients have a high probability of tumor recurrence within the first 5 years after the end of treatment, which is largely driven by CSC activity . The development of new therapeutic strategies targeting TNBC stem cells has thus been intensified over the last years . For example, the kinase inhibitor Dasatinib and TGF‐β pathway inhibition, respectively, were shown to enhance the responsiveness to paclitaxel treatment in preclinical models of TNBC .…”