The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042

Hermida-Prado, Francisco; Villaronga, M. Ángeles; Granda-Díaz, Rocío; Del-Río-Ibisate, Nagore; Santos, Laura; Hermosilla, Maria Ana; Oro, Patricia; Allonca, Eva; Agorreta, Jackeline; Garmendia, Irati; Tornín, Juan; Pérez-Escuredo, Jhudit; Fuente, Rocío Aller de la; Montuenga, Luis M.; Morís, Francisco; Rodrigo, Juan P.; García-Pedrero, Juana M.

doi:10.3390/jcm8081157

Cited by 18 publications

(22 citation statements)

References 49 publications

(64 reference statements)

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“…However, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Recent research proved saracatinib failed to demonstrate monotherapeutic efficacy, with undesirable stem cellpromoting functions in patients with head and neck squamous cell carcinoma [17]. In the present study, we proved the combined treatment of HCC with oxaliplatin and saracatinib impaired the efficacy of either drug individually.…”

Section: Discussionsupporting

confidence: 54%

Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma

Liao

Song

et al. 2020

BMC Cancer

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Background: Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods: The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib-and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ATP-binding cassette transporter G1 (ABCG1) and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.

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Section: Discussionsupporting

confidence: 54%

Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma

Liao

Song

et al. 2020

BMC Cancer

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“…However, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Recent research proved saracatinib failed to demonstrate monotherapeutic efficacy, with undesirable stem cell-promoting functions in patients with head and neck squamous cell carcinoma [18]. In the present study, we proved the combined treatment of HCC with oxaliplatin and saracatinib impaired the efficacy of either drug individually.…”

Section: Discussionsupporting

confidence: 53%

Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma

Liao

Song

Xu³

et al. 2020

Preprint

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Background: Chemo-resistance in hepatocellular carcinoma (HCC) is a major problem, and acquired drug resistance prevents cancer therapies from achieving complete responses. Molecular targeting therapy presents an opportunity to impede tumor through combination or sequential therapy, while the accurate effect is vague. Methods: The efficacy of combinations between oxaliplatin and anti-cancer molecular targeting drugs was screened. Strangely, the combined chemotherapy with oxaliplatin and saracatinib induced significantly antagonistic effects. Then the antitumor effects of combined treatment with saracatinib and oxaliplatin were confirmed in wide type HCC as well as in saracatinib- and oxaliplatin-resistant HCC. RNA sequencing was used to explore the resistance mechanism, and the roles of ABCG1 and Wnt signaling in oxaliplatin resistance were confirmed. Results: Chemotherapy with oxaliplatin and saracatinib individually induced strong anti-HCC effects, while combined or sequential treatment of HCC cells with these two drugs exhibited reduced efficacy compared to treatment with the single drugs. And it was saracatinib treatment caused oxaliplatin resistance. RNA sequencing revealed 458 genes that were altered by treatment with saracatinib and oxaliplatin. Of these, the gene encoding the ATP-binding cassette transporter G1 ABCG1 and Wnt-associated genes were significantly upregulated. Upregulation of ABCG1 and oxaliplatin resistance were associated with activation of Wnt signaling. Interference with ABCG1 expression or inhibition of Wnt signaling resulted in reversal of the saracatinib-induced oxaliplatin resistance in HCC. Conclusions: These studies demonstrated that combined or sequential chemotherapy with oxaliplatin and saracatinib reduced antitumor efficacy, and this antagonism was attributed to the activation of Wnt signaling and upregulation of ABCG1 by saracatinib.

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“…Given the relevant role of SOX2 in tumorigenicity, here we used the SORE6 system [29] to study whether those subpopulations showing SOX2/OCT4 transcriptional activity behave as bona-fide CSCs with higher tumor-initiating potential than other subpopulations. SOX2-based reporter systems were previously used to demonstrate the CSC phenotype of SOX2-expressing subpopulations in glioma, breast, prostate, bladder or head and neck cancers [4,8,24,[26][27][28][29][30][31], although this strategy remained unexplored in sarcomas. In addition, a plasmid containing the human OCT4 promoter driving the expression of GFP was used to show that OCT4-expressing osteosarcoma cells were much more tumorigenic than OCT4 negative cells [22].…”

Section: Discussionmentioning

confidence: 99%

“…Since pluripotency factors are intracellular molecules, the isolation of viable cells expressing these factors cannot be directly achieved using antibody-based flow cytometry. As an alternative method, the use of reporter systems where the expression of a fluorescent protein is driven by the SOX2 and/or OCT4 promoter or by SOX2/OCT4 response elements has proved the tumor-propagating potential of cells expressing pluripotency factors in several tumor models [4,8,22,[24][25][26][27][28][29][30][31]. Notably, this strategy allows the real-time tracking of CSCs and the study of their response to anti-tumor treatments or changes in tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

Menéndez

Rey

Martinez-Cruzado

et al. 2020

Cancers

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Stemness in sarcomas is coordinated by the expression of pluripotency factors, like SOX2, in cancer stem cells (CSC). The role of SOX2 in tumor initiation and progression has been well characterized in osteosarcoma. However, the pro-tumorigenic features of SOX2 have been scarcely investigated in other sarcoma subtypes. Here, we show that SOX2 depletion dramatically reduced the ability of undifferentiated pleomorphic sarcoma (UPS) cells to form tumorspheres and to initiate tumor growth. Conversely, SOX2 overexpression resulted in increased in vivo tumorigenicity. Moreover, using a reporter system (SORE6) which allows to monitor viable cells expressing SOX2 and/or OCT4, we found that SORE6+ cells were significantly more tumorigenic than the SORE6- subpopulation. In agreement with this findings, SOX2 expression in sarcoma patients was associated to tumor grade, differentiation, invasive potential and lower patient survival. Finally, we studied the effect of a panel of anti-tumor drugs on the SORE6+ cells of the UPS model and patient-derived chondrosarcoma lines. We found that the mithramycin analogue EC-8042 was the most efficient in reducing SORE6+ cells in vitro and in vivo. Overall, this study demonstrates that SOX2 is a pro-tumorigenic factor with prognostic potential in sarcoma. Moreover, SORE6 transcriptional activity is a bona fide CSC marker in sarcoma and constitutes an excellent biomarker for evaluating the efficacy of anti-tumor treatments on CSC subpopulations.

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The SRC Inhibitor Dasatinib Induces Stem Cell-Like Properties in Head and Neck Cancer Cells that are Effectively Counteracted by the Mithralog EC-8042

Cited by 18 publications

References 49 publications

Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma

Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma

Oxaliplatin resistance is enhanced by saracatinib via upregulation Wnt-ABCG1 signaling in hepatocellular carcinoma

SOX2 Expression and Transcriptional Activity Identifies a Subpopulation of Cancer Stem Cells in Sarcoma with Prognostic Implications

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