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Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

ABSTRACT: The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.

SUBMITTER: Westbrook TC

PROVIDER: S-EPMC9477876 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

Westbrook Thomas C TC Guan Xiangnan X Rodansky Eva E Flores Diana D Liu Chia Jen CJ Udager Aaron M AM Patel Radhika A RA Haffner Michael C MC Hu Ya-Mei YM Sun Duanchen D Beer Tomasz M TM Foye Adam A Aggarwal Rahul R Quigley David A DA Youngren Jack F JF Ryan Charles J CJ Gleave Martin M Wang Yuzhuo Y Huang Jiaoti J Coleman Ilsa I Morrissey Colm C Nelson Peter S PS Evans Christopher P CP Lara Primo P Reiter Robert E RE Witte Owen O Rettig Matthew M Wong Christopher K CK Weinstein Alana S AS Uzunangelov Vlado V Stuart Josh M JM Thomas George V GV Feng Felix Y FY Small Eric J EJ Yates Joel A JA Xia Zheng Z Alumkal Joshi J JJ

Nature communications 20220915 1

The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progr ...[more]

PMID: 36109521

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Project description:BackgroundPredator-induced defences are a prominent example of phenotypic plasticity found from single-celled organisms to vertebrates. The water flea Daphnia pulex is a very convenient ecological genomic model for studying predator-induced defences as it exhibits substantial morphological changes under predation risk. Most importantly, however, genetically identical clones can be transcriptionally profiled under both control and predation risk conditions and be compared due to the availability of the sequenced reference genome. Earlier gene expression analyses of candidate genes as well as a tiled genomic microarray expression experiment have provided insights into some genes involved in predator-induced phenotypic plasticity. Here we performed the first RNA-Seq analysis to identify genes that were differentially expressed in defended vs. undefended D. pulex specimens in order to explore the genetic mechanisms underlying predator-induced defences at a qualitatively novel level.ResultsWe report 230 differentially expressed genes (158 up- and 72 down-regulated) identified in at least two of three different assembly approaches. Several of the differentially regulated genes belong to families of paralogous genes. The most prominent classes amongst the up-regulated genes include cuticle genes, zinc-metalloproteinases and vitellogenin genes. Furthermore, several genes from this group code for proteins recruited in chromatin-reorganization or regulation of the cell cycle (cyclins). Down-regulated gene classes include C-type lectins, proteins involved in lipogenesis, and other families, some of which encode proteins with no known molecular function.ConclusionsThe RNA-Seq transcriptome data presented in this study provide important insights into gene regulatory patterns underlying predator-induced defences. In particular, we characterized different effector genes and gene families found to be regulated in Daphnia in response to the presence of an invertebrate predator. These effector genes are mostly in agreement with expectations based on observed phenotypic changes including morphological alterations, i.e., expression of proteins involved in formation of protective structures and in cuticle strengthening, as well as proteins required for resource re-allocation. Our findings identify key genetic pathways associated with anti-predator defences.

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Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

Publications

Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.

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