Focal adhesion kinase activation limits efficacy of Dasatinib in c‐Myc driven hepatocellular carcinoma

Liu, Xianqiong; Song, Xinhua; Zhang, Jie; Xu, Zhenhe; Che, Li; Qiao, Yu; Pedraza, Yunuen Ortiz; Cigliano, Antonio; Pascale, Rosa M.; Calvisi, Diego F.; Liu, Yanju; Chen, Xin

doi:10.1002/cam4.1777

Cited by 14 publications

(16 citation statements)

References 37 publications

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“…It was found that the IGF1 was involved in multiple cancer‐related pathways, such as proteoglycans, focal adhesion, and synaptic vesicle cycle. Focal adhesion had been confirmed to regulate cell proliferation, survival, migration, and invasion, which is overexpressed and/or activated in several cancers, including SCLC, colorectal cancer, and hepatocellular carcinoma . Accordingly, we infer that miR‐4784 may promote tumor cell growth and enhance cell invasion.…”

Section: Discussionsupporting

confidence: 92%

Identification of prognostic biomarkers for breast cancer based on miRNA and mRNA co‐expression network

Yao

Liu

Gao

et al. 2019

J of Cellular Biochemistry

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Purpose Breast cancer (BC) remains a serious health threat for women due to its high incidence and the trend of rejuvenation. Accumulating evidence has highlighted that microRNAs (miRNAs) and messenger RNAs (mRNAs) could play important roles in various biological processes involved in the pathogenesis of BC. The present study aimed to identify potential prognostic biomarkers associated with BC. Methods Here, original gene expression profiles of patients with BC was downloaded from The Cancer Genome Atlas (TCGA) database. TargetScan, miRDB, and miRTarBase databases were used to predict the target genes of prognostic‐related differentially expressed miRNAs (DEMs). Subsequently, functional enrichment analysis and topological analysis were performed on the overlaps of target genes and differentially expressed mRNAs (DEGs), and Kaplan‐Meier analysis was used to predict prognosis‐related target genes to identify prognostic biomarkers. Results A total of 218 DEMs and 2222 DEGs were extracted in which eight miRNAs were associated with prognosis, and 278 target DEGs were screened out incorporated into functional enrichment analysis and protein‐protein interaction network visualization studies. Additionally, five hub genes (CXCL12, IGF1, LEF1, MMP1, and RACGAP1) were observed as potential biomarkers for BC prognosis through survival analysis. Conclusion We performed a distinctive correlation analysis of miRNA‐mRNA in BC patients, and identified eight miRNAs and five hub genes may be effective biomarkers for the prognosis of BC patients.

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Section: Discussionsupporting

confidence: 92%

Identification of prognostic biomarkers for breast cancer based on miRNA and mRNA co‐expression network

Yao

Liu

Gao

et al. 2019

J of Cellular Biochemistry

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“…Moreover, in vitro treatment with the combination of defactinib and dasatinib showed drug synergy in the DSRCT, ERMS, and ARMS cells. A similar synergistic effect was previously observed in neuroblastoma, acute lymphoblastic leukemia, and hepatocellular carcinoma (HCC) cells [ 21 , 27 , 32 ]. DSRCT, ERMS, and ARMS cells showed a higher level of drug synergy compared to ES cells.…”

Section: Discussionsupporting

confidence: 80%

“…FAK and Src inhibition, either as a single agent or as part of a combination treatment, has previously been shown to have preclinical effects in a variety of tumor types [ 21 , 25 – 37 ]. In this study, we specifically examined the effects of targeting the FAK-Src complex in pediatric and AYA sarcomas by examining pFAK and pSrc expressions in clinically derived tumor material of DSRCT, ES, ARMS, and ERMS patients and by examining in vitro and in vivo effects of the FAK inhibitor defactinib and the Abl/SFK inhibitor dasatinib combination treatment.…”

Section: Discussionmentioning

confidence: 99%

“…Single-agent defactinib could also have limited clinical effects in DSRCT, ES, and RMS patients as seen previously in non-small cell lung cancer [ 20 ]. In hepatocellular carcinoma, it was shown that dasatinib treatment induced upregulation of activated FAK [ 21 ]. Therefore, we specifically examined the effects of targeting the FAK-Src complex by addressing pFAK and pSrc expressions in clinical tumor sections of primary and post-treatment resections, metastatic and locally recurrent DSRCT ( n = 13), ES ( n = 68), and RMS (ARMS n = 21, ERMS n = 39) and by determining the antitumor effects of the combined treatment of the FAK inhibitor defactinib and the multikinase (Abl/SFK) inhibitor dasatinib in DSRCT, ES, ARMS, and ERMS cell lines.…”

Section: Introductionmentioning

confidence: 99%

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Targeting the FAK-Src Complex in Desmoplastic Small Round Cell Tumors, Ewing Sarcoma, and Rhabdomyosarcoma

Erp¹,

Hillebrandt-Roeffen²,

Bree³

et al. 2022

Sarcoma

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Desmoplastic small round cell tumors (DSRCTs), Ewing sarcoma (ES), and alveolar and embryonal rhabdomyosarcoma (ARMS and ERMS) are malignant sarcomas typically occurring at young age, with a poor prognosis in the metastatic setting. New treatment options are necessary. Src family kinase inhibitor dasatinib single-agent treatment has been investigated in a phase 2 study in patients with advanced sarcomas including ES and RMS but failed as a single agent in these subtypes. Since previous studies demonstrated high FAK and Src activities in RMS and ES tissue and cell lines, and dasatinib treatment was shown to upregulate activated FAK, we hypothesized that FAK-Src combination treatment could potentially be an interesting treatment option for these tumor types. We examined the effects of targeting the FAK-Src complex by addressing (p)FAK and (p)Src expressions in tumor sections of DSRCT (n = 13), ES (n = 68), ARMS (n = 21), and ERMS (n = 39) and by determining the antitumor effects of single and combined treatment with FAK inhibitor defactinib and multikinase (Abl/SFK) inhibitor dasatinib in vitro on cell lines of each subtype. In vivo effects were assessed in DSRCT and ERMS models. Concurrent pFAK and pSrc expressions (H-score >50) were observed in DSRCT (67%), ES (6%), ARMS (35%), and ERMS (19%) samples. Defactinib treatment decreased pFAK expression and reduced cell viability in all subtypes. Dasatinib treatment decreased pSrc expression and cell viability in each subtype. Combination treatment led to a complete reduction in pFAK and pSrc in each cell line and showed enhanced cell viability reduction, drug synergy, DNA damage induction, and a trend toward higher apoptosis induction in DSRCT, ERMS, and ARMS but not in ES cells. These promising in vitro results unfortunately do not translate into promising in vivo results as we did not observe a significant effect on tumor volume in vivo, and the combination did not show superior effects compared to dasatinib single-agent treatment.

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“…7e ). Furthermore, we found that TGFβ1 induced PMEPA1 upregulation in c-MYC high expressed human HCC cell lines (Hep40 and HLF) 37 , but not in c-MYC low expressed human HCC cell lines (Huh7 and SNU475; Fig. 7f–h ), suggesting that PMEPA1 may be a target of TGFβ1 in the context of c-MYC HCC.…”

Section: Resultsmentioning

confidence: 86%

Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression

Wang

et al. 2021

Cell Death Dis

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Dysregulation of transforming growth factor-beta (TGFβ) signaling has been implicated in liver carcinogenesis with both tumor promoting and inhibiting activities. Activation of the c-MYC protooncogene is another critical genetic event in hepatocellular carcinoma (HCC). However, the precise functional crosstalk between c-MYC and TGFβ signaling pathways remains unclear. In the present investigation, we investigated the expression of TGFβ signaling in c-MYC amplified human HCC samples as well as the mechanisms whereby TGFβ modulates c-Myc driven hepatocarcinogenesis during initiation and progression. We found that several TGFβ target genes are overexpressed in human HCCs with c-MYC amplification. In vivo, activation of TGFβ1 impaired c-Myc murine HCC initiation, whereas inhibition of TGFβ pathway accelerated this process. In contrast, overexpression of TGFβ1 enhanced c-Myc HCC progression by promoting tumor cell metastasis. Mechanistically, activation of TGFβ promoted tumor microenvironment reprogramming rather than inducing epithelial-to-mesenchymal transition during HCC progression. Moreover, we identified PMEPA1 as a potential TGFβ1 target. Altogether, our data underline the divergent roles of TGFβ signaling during c-MYC induced HCC initiation and progression.

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Focal adhesion kinase activation limits efficacy of Dasatinib in c‐Myc driven hepatocellular carcinoma

Cited by 14 publications

References 37 publications

Identification of prognostic biomarkers for breast cancer based on miRNA and mRNA co‐expression network

Identification of prognostic biomarkers for breast cancer based on miRNA and mRNA co‐expression network

Targeting the FAK-Src Complex in Desmoplastic Small Round Cell Tumors, Ewing Sarcoma, and Rhabdomyosarcoma

Distinct functions of transforming growth factor-β signaling in c-MYC driven hepatocellular carcinoma initiation and progression

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