Taxane Resistance in Prostate Cancer Mediated by AR-Independent GATA2 Regulation of IGF2

Plymate, Stephen R.; Bhatt, Rupal S.; Balk, Steven P.

doi:10.1016/j.ccell.2015.01.008

Cited by 15 publications

(17 citation statements)

References 10 publications

(11 reference statements)

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“…25,26 Therefore, some degree of cross-resistance has been suggested between AR-targeting therapies and taxane chemotherapies, although this cross-resistance may be less substantial with cabazitaxel than with docetaxel. 27 Recently, work on a particular mouse model of CRPC has also suggested that certain AR-Vs may be associated with sensitivity to taxanes whereas others may mediate taxane resistance.…”

Section: Discussionmentioning

confidence: 99%

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

et al. 2015

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IMPORTANCE We previously showed that detection of androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) from men with castration-resistant prostate cancer (CRPC) was associated with primary resistance to enzalutamide and abiraterone therapy, but the relevance of AR-V7 status in the context of chemotherapy is unknown. OBJECTIVE To investigate whether AR-V7–positive patients would retain sensitivity to taxane chemotherapy and whether AR-V7 status would have a differential impact on taxane-treated men compared with enzalutamide- or abiraterone-treated men. DESIGN, SETTING, AND PARTICIPANTS We examined CTCs for AR-V7 mRNA using a reverse-transcription polymerase chain reaction assay. From January 2013 to July 2014, we prospectively enrolled patients with metastatic CRPC initiating taxane chemotherapy (docetaxel or cabazitaxel) at a single academic institution (Johns Hopkins). Our prespecified statistical plan required a sample size of 36 taxane-treated men. MAIN OUTCOMES AND MEASURES We evaluated associations between AR-V7 status and prostate-specific antigen (PSA) response rates. PSA progression-free survival (PSA PFS), and clinical and/or radiographic progression-free survival (PFS). After incorporating updated data from our prior study of 62 patients treated with enzalutamide or abiraterone, we also investigated the interaction between AR-V7 status (positive or negative) and treatment type (taxane vs enzalutamide or abiraterone). RESULTS Of 37 taxane-treated patients enrolled. 17 (46%) had detectable AR-V7 in CTCs. Prostate-specific antigen responses were achieved in both AR-V7–positive and AR-V7–negative men (41% vs 65%; P = .19) Similarly, PSA PFS (hazard ratio [HR], 1.7, 95% CI, 0.6-5.0; P = .32) and PFS (HR, 2.7, 95% CI, 0.8-8.8; P = .11) were comparable in AR-V7–positive and AR-V7–negative patients. A significant interaction was observed between AR-V7 status and treatment type (P < .001). Clinical outcomes were superior with taxanes compared with enzalutamide or abiraterone therapy in AR-V7–positive men, whereas outcomes did not differ by treatment type in AR-V7–negative men. In AR-V7–positive patients. PSA responses were higher in taxane-treated vs enzalutamide- or abiraterone-treated men (41% vs 0%; P < .001), and PSA PFS and PFS were significantly longer in taxane-treated men (HR, 0.19 [95% CI, 0.07-0.52] for PSA PFS, P = .001; HR, 0.21 [95% CI, 0.07-0.59] for PFS, P = .003). CONCLUSIONS AND RELEVANCE Detection of AR-V7 in CTCs from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy. In AR-V7–positive men, taxanes appear to be more efficacious than enzalutamide or abiraterone therapy, whereas in AR-V7–negative men, taxanes and enzalutamide or abiraterone may have comparable efficacy. Circulating tumor cell–based AR-V7 detection may serve as a treatment selection biomarker in CRPC.

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Section: Discussionmentioning

confidence: 99%

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

et al. 2015

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“…In summary, our study revealed a mechanism for conferring multipotentiality to a progenitor cell population that yields erythroid and myeloid cell progeny. The gene controlled by the −77 element, GATA2 , regulates the development of non–small cell lung cancer ( 50 ), aggressive prostate cancer ( 51 ), primary immunodeficiency, MDS, and myeloid leukemia ( 16 , 44 ). GATA2 is also linked to the development/function of the pituitary ( 52 ) and important components of the nervous system ( 53 ).…”

Section: Discussionmentioning

confidence: 99%

Cis-regulatory mechanisms governing stem and progenitor cell transitions

et al. 2015

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“…It has been proposed that IGF2 encodes a member of the insulin family of polypeptide growth factors, which promote growth-promoting activity possess. Consequently, as an antisense RNA of IGF2, IGF2-AS plays an important role in various cancers, including neuroblastoma and prostate cancer [34,35]. However, the function of IGF2-AS in thyroid carcinoma has not been elucidated yet; larger cohort is needed to testify the role and mechanisms.…”

Section: Lab/in Vitro Researchmentioning

confidence: 99%

Identification of Long Non-Coding RNA Expression Profiles and Co-Expression Genes in Thyroid Carcinoma Based on The Cancer Genome Atlas (TCGA) Database

et al. 2019

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Departmental sources Background: Thyroid carcinoma is a malignancy with high morbidity and mortality. Genetic alterations play pivot roles in the pathogenesis of thyroid carcinoma, where long noncoding RNA (lncRNA) have been identified to be crucial. This study sought to investigate the biological functions of lncRNA expression profiles in thyroid carcinoma. Material/Methods: The lncRNAs expression profiles were acquired from The Cancer Genome Atlas (TCGA) database according to 510 thyroid cancer tissues and 58 normal thyroid tissues. By using R package edgeR, differentially expressed RNAs were obtained. Also, an overall survival model was established based on Cox regression and clinical data then testified by Kaplan-Meier plot, receiver operating characteristic (ROC)-curve and C-index analysis. We investigated the co-expressed genes with lncRNAs involved in the prognostic model, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis was conducted R package clusterProfile. Results: A total of 352 lncRNAs were identified as differentially expressed in thyroid carcinoma, and an overall survival model consisting of 8 signature lncRNAs was proposed (ROC=0.862, C-index=0.893, P<0.05), 3 of which (DOCK9-DT, FAM111A-DT, and LINC01736) represent co-expressed mRNAs. However, as an oncogene, only FAM111A-DT increased the prognostic risk in thyroid carcinoma. Furthermore, we found differential genes LINC01016, LHX1-DT, IGF2-AS, ND MIR1-1HG-AS1, significantly related to lymph node metastasis (P<0.05). Conclusions: In this study, we clarified the differential lncRNA expression profiles which were related to the tumorigenesis and prognosis in thyroid carcinoma. Our results provide new rationale and understandings to the pathogenesis and regulatory mechanisms of thyroid carcinoma.

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Taxane Resistance in Prostate Cancer Mediated by AR-Independent GATA2 Regulation of IGF2

Cited by 15 publications

References 10 publications

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Androgen Receptor Splice Variant 7 and Efficacy of Taxane Chemotherapy in Patients With Metastatic Castration-Resistant Prostate Cancer

Cis-regulatory mechanisms governing stem and progenitor cell transitions

Identification of Long Non-Coding RNA Expression Profiles and Co-Expression Genes in Thyroid Carcinoma Based on The Cancer Genome Atlas (TCGA) Database

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