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LNCAP xenograft prostate cancer progression model in NOD-SCID mice

ABSTRACT: Xenografts are useful in vivo tumour models for investigating cancer progression, therapeutic responses and predicting anti-cancer drug response in patients with cancer of a similar phenotype. We have generated bulk RNA-seq data from LNCaP xenografts of a large and well-annotated prostate cancer progression study, investigating responsiveness and subsequent resistance to therapies targeting the androgen receptor (AR). LNCaP xenograft tumour establishment and initial growth are dependent on androgens in male mice (PRE-CX / pre-castration group). Upon castration, AR activity and tumour growth are suppressed (POST-CX / post-castration group), however, this initial responsiveness to castration reproducibly gives way to castration-resistance (CRPC / castration-resistant prostate cancer). Further treatment of CRPC with the AR targeting drug enzalutamide (ENZ) initially provides a therapeutic response (ENZ Sensitive; ENZS), however, resistance emerges in time (ENZ Resistant; ENZR).

ORGANISM(S): Homo sapiens

PROVIDER: GSE211856 | GEO | 2022/09/07

REPOSITORIES: GEO

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Project description:Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full length (ARFL) or variants (AR-Vs) in disease progression. To define functional roles of ARFL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon 1, intron 1, and exon 8 in AR pre-mRNA to knockdown either ARFL alone, or ARFL plus AR-Vs, and examined their respective effects in LNCaP-derived ENZ-R, as well as M12 and 22Rv1, cells. ENZ-R LNCaP xenografts express high levels of both ARFL and AR-V7 compared to CRPC LNCaP xenografts. In particular, ARFL levels were ~20-fold higher than AR-V7. ENZ-R LNCaP sub-lines, derived by selection from the ENZ xenografts, also expressed uniformly high levels of ARFL and AR-V7 compared to CRPC LNCaP cells. In addition, both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP. In ENZ-R LNCaP cells, knockdown of ARFL alone, or ARFL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression in vitro, and delayed tumour growth in vivo. In 22Rv1 cells that are inherently resistant to ENZ, knockdown of both ARFL and AR-Vs more potently suppressed cell growth, AR transcriptional activity and AR-regulated gene expression than knockdown of ARFL alone. These data indicate the AR is an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both ARFL and AR-Vs is a rational approach for AR-dependent CRPC. CRPC and ENZ-R LNCaP xenografts were generated as described in: Gleave, M.E., et al., Serum prostate specific antigen levels in mice bearing human prostate LNCaP tumors are determined by tumor volume and endocrine and growth factors. Cancer Res, 1992. 52(6): p. 1598-605.

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LNCAP xenograft prostate cancer progression model in NOD-SCID mice

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