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A forward genetics screen identifies modifiers of Rocaglate responsiveness

ABSTRACT: A forward genetics screen identifies modifiers of Rocaglate responsiveness

PROVIDER: PRJNA703979 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13764262_1.fastq.gz	Fastqsanger.gz
	SRR13764262_2.fastq.gz	Fastqsanger.gz
	SRR13764263_1.fastq.gz	Fastqsanger.gz
	SRR13764263_2.fastq.gz	Fastqsanger.gz
	SRR13764264_1.fastq.gz	Fastqsanger.gz

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A forward genetics screen identifies modifiers of Rocaglate responsiveness

Project description:Rocaglates are a class of eukaryotic translation initiation inhibitors that are being explored as chemotherapeutic agents. They function by targeting eukaryotic initiation factor (eIF) 4A, an RNA helicase critical for recruitment of the 40S ribosome (and associated factors) to mRNA templates. To appreciate how rocaglates could best be enabled in the clinic, an understanding of resistance mechanisms is important, as this could inform on strategies to bypass such events as well as responsive tumor types. In performing a forward genetics screen using a cDNA library, we identified FOXP3 to be a gene of interest. As FOXP3 is a known transcriptional regulator, understandings its impacts on the transcriptional landscape was a logical undertaking in elucidating the resistance mechanis. Here, we report on the RNAseq results in Hap1 cells overexpressing FOXP3 compared to a negative control cell line expressing GFP. We find that certain genes involved in response to drug, such as ABCB1 (P-glycoprotein), are potently upregulated in a FOXP3-overexpression setting.

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A forward genetic screen identifies modifiers of rocaglate responsiveness.

Project description:Rocaglates are a class of eukaryotic translation initiation inhibitors that are being explored as chemotherapeutic agents. They function by targeting eukaryotic initiation factor (eIF) 4A, an RNA helicase critical for recruitment of the 40S ribosome (and associated factors) to mRNA templates. Rocaglates perturb eIF4A activity by imparting a gain-of-function activity to eIF4A and mediating clamping to RNA. To appreciate how rocaglates could best be enabled in the clinic, an understanding of resistance mechanisms is important, as this could inform on strategies to bypass such events as well as identify responsive tumor types. Here, we report on the results of a positive selection, ORFeome screen aimed at identifying cDNAs capable of conferring resistance to rocaglates. Two of the most potent modifiers of rocaglate response identified were the transcription factors FOXP3 and NR1I3, both of which have been implicated in ABCB1 regulation-the gene encoding P-glycoprotein (Pgp). Pgp has previously been implicated in conferring resistance to silvestrol, a naturally occurring rocaglate, and we show here that this extends to additional synthetic rocaglate derivatives. In addition, FOXP3 and NR1I3 impart a multi-drug resistant phenotype that is reversed upon inhibition of Pgp, suggesting a potential therapeutic combination strategy.

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