Abstract
Docetaxel chemotherapy in metastatic prostate cancer offers only a modest survival benefit because of emerging resistance. To identify candidate therapeutic gene targets, we applied a murine prostate cancer orthograft model that recapitulates clinical invasive prostate cancer in a genome-wide CRISPR/Cas9 screen under docetaxel treatment pressure. We identified 17 candidate genes whose suppression may enhance the efficacy of docetaxel, with transcription elongation factor A-like 1 (Tceal1) as the top candidate. TCEAL1 function is not fully characterised; it may modulate transcription in a promoter dependent fashion. Suppressed TCEAL1 expression in multiple human prostate cancer cell lines enhanced therapeutic response to docetaxel. Based on gene set enrichment analysis from transcriptomic data and flow cytometry, we confirmed that loss of TCEAL1 in combination with docetaxel leads to an altered cell cycle profile compared with docetaxel alone, with increased subG1 cell death and increased polyploidy. Here, we report the first in vivo genome-wide treatment sensitisation CRISPR screen in prostate cancer, and present proof of concept data on TCEAL1 as a candidate for a combinational strategy with the use of docetaxel.
Highlights
Prostate cancer is the second most common cause of cancer deaths in men in the Western world [1]
We further identified cell cycle alterations to be associated with enhanced treatment response upon combined TCEAL1 silencing and docetaxel treatment
Prostate tumour weights were higher in the SP mice than those with Pten deletion alone (Fig 1B), suggesting that combined altered RAS/ERK and PI3K/AKT signalling promotes prostate tumorigenesis
Summary
Prostate cancer is the second most common cause of cancer deaths in men in the Western world [1]. Androgen deprivation therapy (ADT) remains the first-line hormonal treatment option, whereas docetaxel is currently the standard chemotherapy drug routinely used to treat metastatic prostate cancer. Leads to only a modest increase in median survival of 10 mo [2]. A second-line chemotherapy drug, cabazitaxel, has been approved. Cabazitaxel only offers a modest survival benefit of just 2.4 mo [3]. Recent evidence from clinical trials giving hormone-sensitive patients upfront treatment of docetaxel in combination with ADT has demonstrated a robust increase in survival. Upfront ADT combination therapy with either chemotherapy or androgen receptor (AR) pathway inhibitors has become routinely used [2, 4, 5, 6]. There is an unmet need for additional combination approaches to improve the efficacy of docetaxel
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