Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

Doheny, Daniel; Sirkisoon, Sherona; Carpenter, Richard L.; Aguayo, Noah R.; Regua, Angelina T.; Anguelov, Marlyn; Manore, Sara G.; Arrigo, Austin; Jalboush, Sara Abu; Wong, Grace Lai Hung; Yu, Yang; Wagner, Calvin J.; Chan, Michael D.; Ruiz, Jimmy; Thomas, Alexandra; Strowd, Roy; Lin, Jiayuh; Lo, Hui-Wen

doi:10.1038/s41388-020-01454-1

Cited by 57 publications

(38 citation statements)

References 77 publications

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“…It plays an important role in cytokine signal transduction and regulation of cell growth and gene expression. JAK2 inhibitors cooperate with SMO inhibitors to inhibit the growth and metastasis of breast cancer cells (Doheny et al, 2020 ). Ito et al ( 2004 ) detected the expression of JAK2 in mouse embryos to understand the role of JAK2 in the regulation of early preimplantation development by reverse transcription–polymerase chain reaction analysis and immunocytochemistry and found that JAK2 was mainly localized in single-cell embryos.…”

Section: Discussionmentioning

confidence: 99%

Construction of Circular RNA–MicroRNA–Messenger RNA Regulatory Network of Recurrent Implantation Failure to Explore Its Potential Pathogenesis

et al. 2021

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Background: Many studies on circular RNAs (circRNAs) have recently been published. However, the function of circRNAs in recurrent implantation failure (RIF) is unknown and remains to be explored. This study aims to determine the regulatory mechanisms of circRNAs in RIF.Methods: Microarray data of RIF circRNA (GSE147442), microRNA (miRNA; GSE71332), and messenger RNA (mRNA; GSE103465) were downloaded from the Gene Expression Omnibus (GEO) database to identify differentially expressed circRNA, miRNA, and mRNA. The circRNA–miRNA–mRNA network was constructed by Cytoscape 3.8.0 software, then the protein–protein interaction (PPI) network was constructed by STRING database, and the hub genes were identified by cytoHubba plug-in. The circRNA–miRNA–hub gene regulatory subnetwork was formed to understand the regulatory axis of hub genes in RIF. Finally, the Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the hub genes were performed by clusterProfiler package of Rstudio software, and Reactome Functional Interaction (FI) plug-in was used for reactome analysis to comprehensively analyze the mechanism of hub genes in RIF.Results: A total of eight upregulated differentially expressed circRNAs (DECs), five downregulated DECs, 56 downregulated differentially expressed miRNAs (DEmiRs), 104 upregulated DEmiRs, 429 upregulated differentially expressed genes (DEGs), and 1,067 downregulated DEGs were identified regarding RIF. The miRNA response elements of 13 DECs were then predicted. Seven overlapping miRNAs were obtained by intersecting the predicted miRNA and DEmiRs. Then, 56 overlapping mRNAs were obtained by intersecting the predicted target mRNAs of seven miRNAs with 1,496 DEGs. The circRNA–miRNA–mRNA network and PPI network were constructed through six circRNAs, seven miRNAs, and 56 mRNAs; and four hub genes (YWHAZ, JAK2, MYH9, and RAP2C) were identified. The circRNA–miRNA–hub gene regulatory subnetwork with nine regulatory axes was formed in RIF. Functional enrichment analysis and reactome analysis showed that these four hub genes were closely related to the biological functions and pathways of RIF.Conclusion: The results of this study provide further understanding of the potential pathogenesis from the perspective of circRNA-related competitive endogenous RNA network in RIF.

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Section: Discussionmentioning

confidence: 99%

Construction of Circular RNA–MicroRNA–Messenger RNA Regulatory Network of Recurrent Implantation Failure to Explore Its Potential Pathogenesis

et al. 2021

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“…These pathways are downstream of EGFR and also have been shown to cross-talk with DNA repair pathways [ 41 – 44 ]. In addition to DNA repair, the JAK/STAT pathway has also been shown to affect the expression of genes controlling immune signaling, including PD-L1 [ 45 ], as well as modulate the stemness of TNBC cells [ 46 ]. A recent phase 2 study of ruxolitinib monotherapy in TNBC has been reported [ 47 ], and despite on-target inhibition, the study did not meet its efficacy endpoint.…”

Section: Discussionmentioning

confidence: 99%

An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

et al. 2021

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Background Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Methods A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. Results Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. Trial registration ClinicalTrials.gov, NCT02158507. Registered on 12 September 2014

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“…Flow cytometry for CD44 high /CD24 low cells and mammosphere assays were performed as previously described [ 65 ]. For ALDH activity, BT20 cells were transfected for 24 h and seeded in mammosphere conditions for up five days.…”

Section: Methodsmentioning

confidence: 99%

TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers

Regua

Aguayo

Jalboush

et al. 2021

Cancers

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JAK2–STAT3 and TrkA signaling pathways have been separately implicated in aggressive breast cancers; however, whether they are co-activated or undergo functional interaction has not been thoroughly investigated. Herein we report, for the first time that STAT3 and TrkA are significantly co-overexpressed and co-activated in triple-negative breast cancer (TNBC) and HER2-enriched breast cancer, as shown by immunohistochemical staining and data mining. Through immunofluorescence staining–confocal microscopy and immunoprecipitation–Western blotting, we found that TrkA and STAT3 co-localize and physically interact in the cytoplasm, and the interaction is dependent on STAT3-Y705 phosphorylation. TrkA–STAT3 interaction leads to STAT3 phosphorylation at Y705 by TrkA in breast cancer cells and cell-free kinase assays, indicating that STAT3 is a novel substrate of TrkA. β-NGF-mediated TrkA activation induces TrkA–STAT3 interaction, STAT3 nuclear transport and transcriptional activity, and the expression of STAT3 target genes, SOX2 and MYC. The co-activation of both pathways promotes breast cancer stem cells. Finally, we found that TNBC and HER2-enriched breast cancer with JAK2–STAT3 and TrkA co-activation are positively associated with poor overall metastasis-free and organ-specific metastasis-free survival. Collectively, our study uncovered that TrkA is a novel activating kinase of STAT3, and their co-activation enhances gene transcription and promotes breast cancer stem cells in TNBC and HER2-enriched breast cancer.

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Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

Cited by 57 publications

References 77 publications

Construction of Circular RNA–MicroRNA–Messenger RNA Regulatory Network of Recurrent Implantation Failure to Explore Its Potential Pathogenesis

Construction of Circular RNA–MicroRNA–Messenger RNA Regulatory Network of Recurrent Implantation Failure to Explore Its Potential Pathogenesis

An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

TrkA Interacts with and Phosphorylates STAT3 to Enhance Gene Transcription and Promote Breast Cancer Stem Cells in Triple-Negative and HER2-Enriched Breast Cancers

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