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Article ; Online: High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer.

2023 Volume 42, Issue 8, Page(s) 112821

Abstract: Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor- ... ...

Abstract	Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.
Language	English
Publishing date	2023-07-18
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112821
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer.

Veeraraghavan, Jamunarani / Gutierrez, Carolina / De Angelis, Carmine / Davis, Robert / Wang, Tao / Pascual, Tomas / Selenica, Pier / Sanchez, Katherine / Nitta, Hiroaki / Kapadia, Monesh / Pavlick, Anne C / Galvan, Patricia / Rexer, Brent / Forero-Torres, Andres / Nanda, Rita / Storniolo, Anna M / Krop, Ian E / Goetz, Matthew P / Nangia, Julie R /

Wolff, Antonio C / Weigelt, Britta / Reis-Filho, Jorge S / Hilsenbeck, Susan G / Prat, Aleix / Osborne, C Kent / Schiff, Rachel / Rimawi, Mothaffar F

Clinical cancer research : an official journal of the American Association for Cancer Research

2024 Volume 29, Issue 16, Page(s) 3101–3109

Abstract: Purpose: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with ... ...

Abstract	Purpose: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy. Experimental design: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. Results: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. Conclusions: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.
MeSH term(s)	Female ; Humans ; Antineoplastic Combined Chemotherapy Protocols ; Biomarkers, Tumor/metabolism ; Breast Neoplasms/diagnosis ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Class I Phosphatidylinositol 3-Kinases/genetics ; Lapatinib ; Neoadjuvant Therapy ; Quinazolines ; Receptor, ErbB-2/metabolism ; Trastuzumab ; Treatment Outcome
Chemical Substances	Biomarkers, Tumor ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Lapatinib (0VUA21238F) ; Quinazolines ; Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-22-3753
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Article ; Online: A Novel Neoplastic Fusion Transcript,

Liu, Chia-Chia / Veeraraghavan, Jamunarani / Tan, Ying / Kim, Jin-Ah / Wang, Xian / Loo, Suet Kee / Lee, Sanghoon / Hu, Yiheng / Wang, Xiao-Song

Clinical cancer research : an official journal of the American Association for Cancer Research

2020 Volume 27, Issue 3, Page(s) 785–798

Abstract: Purpose: Luminal B breast tumors are more aggressive estrogen receptor-positive (ER: Experimental design: We performed large-scale RNA sequencing analysis to identify chimerical transcripts preferentially expressed in luminal B breast cancer. The ... ...

Abstract	Purpose: Luminal B breast tumors are more aggressive estrogen receptor-positive (ER Experimental design: We performed large-scale RNA sequencing analysis to identify chimerical transcripts preferentially expressed in luminal B breast cancer. The lead candidate was validated by reverse transcription PCR in breast cancer tissues. The effects of inducible ectopic expression or genetic silencing were assessed by phenotypic assays such as MTS, transwell, and transendothelial migration assays, and by clonogenic assays to assess MEK inhibitor sensitivity. Subcellular fractionation, Western blots, and immunoprecipitation were performed to characterize the protein products and elucidate the engaged mechanisms. Results: Here we report a novel tumor-specific chimeric transcript Conclusions: This discovery sheds light on a new area of molecular pathobiology of luminal B tumors and implies potential new therapeutic opportunities for more aggressive breast tumors overexpressing this fusion.
MeSH term(s)	Breast/pathology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Cell Line, Tumor ; DNA-Binding Proteins/genetics ; Datasets as Topic ; Drug Resistance, Neoplasm/genetics ; Female ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; MAP Kinase Signaling System/drug effects ; MAP Kinase Signaling System/genetics ; Mitogen-Activated Protein Kinase Kinases/metabolism ; Oncogene Proteins, Fusion/genetics ; Protein Serine-Threonine Kinases/genetics ; Protein-Tyrosine Kinases/genetics ; Pyridones/pharmacology ; Pyridones/therapeutic use ; Pyrimidinones/pharmacology ; Pyrimidinones/therapeutic use ; RNA-Binding Proteins/genetics ; RNA-Seq ; Dyrk Kinases
Chemical Substances	DNA-Binding Proteins ; Oncogene Proteins, Fusion ; Pyridones ; Pyrimidinones ; RAD51AP1 protein, human ; RNA-Binding Proteins ; trametinib (33E86K87QN) ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2)
Language	English
Publishing date	2020-11-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-2769
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Article ; Online: High FOXA1 levels induce ER transcriptional reprogramming, a pro-metastatic secretome, and metastasis in endocrine-resistant breast cancer

Cell Reports, Vol 42, Iss 8, Pp 112821- (2023)

2023

Abstract: Summary: Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen ... ...

Abstract	Summary: Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near Secretome14 genes is also increased in mutant ER-expressing or mitogen-treated ER+ BC cells and in ER+ metastatic vs. primary tumors, suggesting a convergent pathway including high growth factor receptor signaling in activating pro-metastatic secretome genes. Our findings uncover H-FOXA1-induced ER reprogramming that drives EndoR and metastasis partly via an H-FOXA1/ER-dependent secretome.
Keywords	CP: Cancer ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2023-08-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: Therapeutic role of recurrent ESR1-CCDC170 gene fusions in breast cancer endocrine resistance.

Li, Li / Lin, Ling / Veeraraghavan, Jamunarani / Hu, Yiheng / Wang, Xian / Lee, Sanghoon / Tan, Ying / Schiff, Rachel / Wang, Xiao-Song

Breast cancer research : BCR

2020 Volume 22, Issue 1, Page(s) 84

Abstract: Background: Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies ... ...

Abstract	Background: Endocrine therapy is the most common treatment for estrogen receptor (ER)-positive breast cancer, but its effectiveness is limited by high rates of primary and acquired resistance. There are likely many genetic causes, and recent studies suggest the important role of ESR1 mutations and fusions in endocrine resistance. Previously, we reported a recurrent ESR1 fusion called ESR1-CCDC170 in 6-8% of the luminal B breast cancers that has a worse clinical outcome after endocrine therapy. Despite being the most frequent ESR1 fusion, its functional role in endocrine resistance has not been studied in vivo, and the engaged mechanism and therapeutic relevance remain uncharacterized. Methods: The endocrine sensitivities of HCC1428 or T47D breast cancer cells following genetic perturbations of ESR1-CCDC170 were assessed using clonogenic assays and/or xenograft mouse models. The underlying mechanisms were investigated by reverse phase protein array, western blotting, immunoprecipitation, and bimolecular fluorescence complementation assays. The sensitivity of ESR1-CCDC170 expressing breast cancer cells to concomitant treatments of tamoxifen and HER/SRC inhibitors was assessed by clonogenic assays. Results: Our results suggested that different ESR1-CCDC170 fusions endow different levels of reduced endocrine sensitivity in vivo, resulting in significant survival disadvantages. Further investigation revealed a novel mechanism that ESR1-CCDC170 binds to HER2/HER3/SRC and activates SRC/PI3K/AKT signaling. Silencing of ESR1-CCDC170 in the fusion-positive cell line, HCC1428, downregulates HER2/HER3, represses pSRC/pAKT, and improves endocrine sensitivity. More important, breast cancer cells expressing ectopic or endogenous ESR1-CCDC170 are highly sensitive to treatment regimens combining endocrine agents with the HER2 inhibitor lapatinib and/or the SRC inhibitor dasatinib. Conclusion: ESR1-CCDC170 may endow breast cancer cell survival under endocrine therapy via maintaining/activating HER2/HER3/SRC/AKT signaling which implies a potential therapeutic strategy for managing these fusion positive tumors.
MeSH term(s)	Animals ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Breast Neoplasms/drug therapy ; Breast Neoplasms/genetics ; Breast Neoplasms/pathology ; Carrier Proteins/genetics ; Cell Line, Tumor ; Dasatinib/administration & dosage ; Drug Resistance, Neoplasm ; Estrogen Receptor alpha/genetics ; Female ; Fulvestrant/administration & dosage ; Humans ; Lapatinib/administration & dosage ; Mice ; Mice, Nude ; Oncogene Proteins, Fusion ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/metabolism ; Signal Transduction ; Tamoxifen/administration & dosage ; Xenograft Model Antitumor Assays ; src-Family Kinases/antagonists & inhibitors ; src-Family Kinases/metabolism
Chemical Substances	CCDC170 protein, human ; Carrier Proteins ; ESR1 protein, human ; Estrogen Receptor alpha ; Oncogene Proteins, Fusion ; Tamoxifen (094ZI81Y45) ; Lapatinib (0VUA21238F) ; Fulvestrant (22X328QOC4) ; ERBB2 protein, human (EC 2.7.10.1) ; Receptor, ErbB-2 (EC 2.7.10.1) ; src-Family Kinases (EC 2.7.10.2) ; Dasatinib (RBZ1571X5H)
Language	English
Publishing date	2020-08-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2015059-3
ISSN	1465-542X ; 1465-5411
ISSN (online)	1465-542X
ISSN	1465-5411
DOI	10.1186/s13058-020-01325-3
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Zs.A 5494: Show issues

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Article ; Online: Recurrent and pathological gene fusions in breast cancer: current advances in genomic discovery and clinical implications.

Veeraraghavan, Jamunarani / Ma, Jiacheng / Hu, Yiheng / Wang, Xiao-Song

Breast cancer research and treatment

2016 Volume 158, Issue 2, Page(s) 219–232

Abstract: Gene fusions have long been considered principally as the oncogenic events of hematologic malignancies, but have recently gained wide attention in solid tumors due to several milestone discoveries and the advancement of deep sequencing technologies. With ...

Abstract	Gene fusions have long been considered principally as the oncogenic events of hematologic malignancies, but have recently gained wide attention in solid tumors due to several milestone discoveries and the advancement of deep sequencing technologies. With the progress in deep sequencing studies of breast cancer transcriptomes and genomes, the discovery of recurrent and pathological gene fusions in breast cancer is on the focus. Recently, driven by new deep sequencing studies, several recurrent or pathological gene fusions have been identified in breast cancer, including ESR1-CCDC170, SEC16A-NOTCH1, SEC22B-NOTCH2, and ESR1-YAP1 etc. More important, most of these gene fusions are preferentially identified in the more aggressive breast cancers, such as luminal B, basal-like, or endocrine-resistant breast cancer, suggesting recurrent gene fusions as additional key driver events in these tumors other than the known drivers such as the estrogen receptor. In this paper, we have comprehensively summarized the newly identified recurrent or pathological gene fusion events in breast cancer, reviewed the contributions of new genomic and deep sequencing technologies to new fusion discovery and the integrative bioinformatics tools to analyze these data, highlighted the biological relevance and clinical implications of these fusion discoveries, and discussed future directions of gene fusion research in breast cancer.
Language	English
Publishing date	2016-07
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	604563-7
ISSN	1573-7217 ; 0167-6806
ISSN (online)	1573-7217
ISSN	0167-6806
DOI	10.1007/s10549-016-3876-y
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Zs.A 1655: Show issues

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Article ; Online: Towards personalized treatment for early stage HER2-positive breast cancer.

Goutsouliak, Kristina / Veeraraghavan, Jamunarani / Sethunath, Vidyalakshmi / De Angelis, Carmine / Osborne, C Kent / Rimawi, Mothaffar F / Schiff, Rachel

Nature reviews. Clinical oncology

2019 Volume 17, Issue 4, Page(s) 233–250

Abstract: Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti- ... ...

Abstract	Advances in HER2-targeted therapies have improved the survival of patients with HER2-positive breast cancer. The standard-of-care treatment for localized disease has been chemotherapy and 1 year of adjuvant HER2-targeted therapy, typically with the anti-HER2 antibody trastuzumab. Despite the effectiveness of this treatment, disease relapse occurs in a subset of patients; thus, focus has been placed on escalating treatment by either combining different HER2-targeted agents or extending the duration of HER2-targeted therapy. Indeed, dual HER2-targeted therapies and extended-duration anti-HER2 therapy, as well as adjuvant therapy with the anti-HER2 antibody-drug conjugate T-DM1, have all been approved for clinical use. Emerging evidence suggests, however, that some patients do not derive sufficient benefit from these additional therapies to offset the associated toxicities and/or costs. Similarly, the universal use of chemotherapy might not benefit all patients, and treatment de-escalation through omission of chemotherapy has shown promise in clinical trials and is currently being explored further. The future of precision medicine should therefore involve tailoring of therapy based on the genetics and biology of each tumour and the clinical characteristics of each patient. Predictive biomarkers that enable the identification of patients who will benefit from either escalated or de-escalated treatment will be crucial to this approach. In this Review, we summarize the available HER2-targeted agents and associated mechanisms of resistance, and describe the current therapeutic landscape of early stage HER2-positive breast cancer, focusing on strategies for treatment escalation or de-escalation.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Breast Neoplasms/drug therapy ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Chemotherapy, Adjuvant ; Female ; Humans ; Molecular Targeted Therapy/methods ; Neoplasm Staging ; Precision Medicine/methods ; Receptor, ErbB-2/antagonists & inhibitors ; Receptor, ErbB-2/metabolism ; Trastuzumab/administration & dosage ; Trastuzumab/therapeutic use
Chemical Substances	Receptor, ErbB-2 (EC 2.7.10.1) ; Trastuzumab (P188ANX8CK)
Language	English
Publishing date	2019-12-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	2491410-1
ISSN	1759-4782 ; 1759-4774
ISSN (online)	1759-4782
ISSN	1759-4774
DOI	10.1038/s41571-019-0299-9
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Zs.A 6029: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MG 103: Show issues

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Article ; Online: Amplification of TLK2 Induces Genomic Instability via Impairing the G2-M Checkpoint.

Kim, Jin-Ah / Anurag, Meenakshi / Veeraraghavan, Jamunarani / Schiff, Rachel / Li, Kaiyi / Wang, Xiao-Song

Molecular cancer research : MCR

2016 Volume 14, Issue 10, Page(s) 920–927

Abstract: Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in clinics. Previously, we described that a cell cycle-associated kinase called Tousled-like kinase 2 (TLK2) is frequently deregulated by genomic ... ...

Abstract	Managing aggressive breast cancers with enhanced chromosomal instability (CIN) is a significant challenge in clinics. Previously, we described that a cell cycle-associated kinase called Tousled-like kinase 2 (TLK2) is frequently deregulated by genomic amplifications in aggressive estrogen receptor-positive (ER Implications: Targeting TLK2 presents an attractive therapeutic strategy for the TLK2-amplified breast cancers that possess enhanced genomic instability and aggressiveness. Mol Cancer Res; 14(10); 920-7. ©2016 AACR.
MeSH term(s)	Breast Neoplasms/genetics ; Cell Line, Tumor ; DNA Damage ; Female ; G2 Phase Cell Cycle Checkpoints ; Gene Amplification ; Gene Expression Regulation, Neoplastic ; Genomic Instability ; Humans ; Protein Kinases/genetics ; Up-Regulation
Chemical Substances	Protein Kinases (EC 2.7.-) ; protein kinase U (EC 2.7.1.-)
Language	English
Publishing date	2016-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-16-0161
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Zs.A 5744: Show issues

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Article ; Online: Therapeutic Targeting of Nemo-like Kinase in Primary and Acquired Endocrine-resistant Breast Cancer.

Wang, Xian / Veeraraghavan, Jamunarani / Liu, Chia-Chia / Cao, Xixi / Qin, Lanfang / Kim, Jin-Ah / Tan, Ying / Loo, Suet Kee / Hu, Yiheng / Lin, Ling / Lee, Sanghoon / Shea, Martin J / Mitchell, Tamika / Li, Shunqiang / Ellis, Matthew J / Hilsenbeck, Susan G / Schiff, Rachel / Wang, Xiao-Song

Clinical cancer research : an official journal of the American Association for Cancer Research

2021 Volume 27, Issue 9, Page(s) 2648–2662

Abstract: Purpose: Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)-positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There ... ...

Abstract	Purpose: Endocrine resistance remains a major clinical challenge in estrogen receptor (ER)-positive breast cancer. Despite the encouraging results from clinical trials for the drugs targeting known survival signaling, relapse is still inevitable. There is an unmet need to discover new drug targets in the unknown escape pathways. Here, we report Nemo-like kinase (NLK) as a new actionable kinase target that endows previously uncharacterized survival signaling in endocrine-resistant breast cancer. Experimental design: The effects of NLK inhibition on the viability of endocrine-resistant breast cancer cell lines were examined by MTS assay. The effect of VX-702 on NLK activity was verified by kinase assay. The modulation of ER and its coactivator, SRC-3, by NLK was examined by immunoprecipitation, kinase assay, luciferase assay, and RNA sequencing. The therapeutic effects of VX-702 and everolimus were tested on cell line- and patient-derived xenograft (PDX) tumor models. Results: NLK overexpression endows reduced endocrine responsiveness and is associated with worse outcome of patients treated with tamoxifen. Mechanistically, NLK may function, at least in part, via enhancing the phosphorylation of ERα and its key coactivator, SRC-3, to modulate ERα transcriptional activity. Through interrogation of a kinase profiling database, we uncovered and verified a highly selective dual p38/NLK inhibitor, VX-702. Coadministration of VX-702 with the mTOR inhibitor, everolimus, demonstrated a significant therapeutic effect in cell line-derived xenograft and PDX tumor models of acquired or Conclusions: Together, this study reveals the potential of therapeutic modulation of NLK for the management of the endocrine-resistant breast cancers with active NLK signaling.
MeSH term(s)	Animals ; Antineoplastic Agents, Hormonal/pharmacology ; Antineoplastic Agents, Hormonal/therapeutic use ; Biomarkers, Tumor ; Breast Neoplasms/diagnosis ; Breast Neoplasms/drug therapy ; Breast Neoplasms/etiology ; Breast Neoplasms/metabolism ; Cell Line, Tumor ; Cell Survival/drug effects ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Drug Resistance, Neoplasm/drug effects ; Estrogen Receptor alpha/metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Humans ; Mice ; Phosphorylation ; Prognosis ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Protein Serine-Threonine Kinases/metabolism ; Signal Transduction/drug effects ; Xenograft Model Antitumor Assays
Chemical Substances	Antineoplastic Agents, Hormonal ; Biomarkers, Tumor ; Estrogen Receptor alpha ; Protein Kinase Inhibitors ; NLK protein, human (EC 2.7.1.-) ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2021-02-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-20-2961
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Article ; Online: Correction: Activation of the IFN Signaling Pathway is Associated with Resistance to CDK4/6 Inhibitors and Immune Checkpoint Activation in ER-Positive Breast Cancer.

De Angelis, Carmine / Fu, Xiaoyong / Cataldo, Maria Letizia / Nardone, Agostina / Pereira, Resel / Veeraraghavan, Jamunarani / Nanda, Sarmistha / Qin, Lanfang / Sethunath, Vidyalakshmi / Wang, Tao / Hilsenbeck, Susan G / Benelli, Matteo / Migliaccio, Ilenia / Guarducci, Cristina / Malorni, Luca / Litchfield, Lacey M / Liu, Jiangang / Donaldson, Joshua / Selenica, Pier /

Brown, David N / Weigelt, Britta / Reis-Filho, Jorge S / Park, Ben H / Hurvitz, Sara A / Slamon, Dennis J / Rimawi, Mothaffar F / Jansen, Valerie M / Jeselsohn, Rinath / Osborne, C Kent / Schiff, Rachel

Clinical cancer research : an official journal of the American Association for Cancer Research

2021 Volume 27, Issue 17, Page(s) 4939

Language	English
Publishing date	2021-09-01
Publishing country	United States
Document type	Journal Article ; Published Erratum
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-21-2431
Database	MEDical Literature Analysis and Retrieval System OnLINE

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