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Genetic screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

ABSTRACT: Genetic screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

PROVIDER: PRJNA772940 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR16495866_1.fastq.gz	Fastqsanger.gz
	SRR16495866_2.fastq.gz	Fastqsanger.gz
	SRR16495867_1.fastq.gz	Fastqsanger.gz
	SRR16495867_2.fastq.gz	Fastqsanger.gz
	SRR16495868_1.fastq.gz	Fastqsanger.gz

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RNA interference screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells.

Project description:RationalePI3K/mTOR signaling is frequently upregulated in breast cancer making inhibitors of this pathway highly promising anticancer drugs. However, PI3K-inhibitors have a low therapeutic index. Therefore, finding novel combinatory treatment options represents an important step towards clinical implementation of PI3K pathway inhibition in breast cancer therapy. Here, we propose proteases as potential synergistic partners with simultaneous PI3K inhibition in breast cancer cells.MethodsWe performed mRNA expression studies and unbiased functional genetic synthetic lethality screens by a miR-E based knockdown system targeting all genome-encoded proteases, i.e. the degradome of breast cancer cells. Importantly theses RNA interference screens were done in combination with two PI3K pathway inhibitors. Protease hits were validated in human and murine breast cancer cell lines as well as in non-cancerous cells by viability and growth assays.ResultsThe degradome-wide genetic screens identified 181 proteases that influenced susceptibility of murine breast cancer cells to low dose PI3K inhibition. Employing independently generated inducible knockdown cell lines we validated 12 protease hits in breast cancer cells. In line with the known tumor promoting function of these proteases we demonstrated Usp7 and Metap2 to be important for murine and human breast cancer cell growth and discovered a role for Metap1 in this context. Most importantly, we demonstrated that Usp7, Metap1 or Metap2 knockdown combined with simultaneous PI3K inhibition resulted in synergistic impairment of murine and human breast cancer cell growth Conclusion: We successfully established proteases as combinatory targets with PI3K inhibition in human and murine breast cancer cells. Usp7, Metap1 and Metap2 are synthetic lethal partners of simultaneous protease/PI3K inhibition, which may refine future breast cancer therapy.

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Genetic screens discover proteases as synthetic lethal partners of PI3K inhibition in breast cancer cells

Project description:The RNA-Seq analysed the changes in protease gene expression upon short-term PI3K inhibition in three breast cancer cell lines.

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G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

Project description:G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

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G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

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G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

Project description:G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

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G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

Project description:Neurofibromatosis Type II is a genetic condition caused by loss of the NF2 gene, resulting in activation of the YAP/TAZ pathway and recurrent growth of benign tumors from Schwann cells, the glia of the peripheral nervous system. Unfortunately, no pharmacological therapy is currently available for NFII. Here, we undertake a genome-wide CRISPR/cas9 screen to search for synthetic-lethal genes that, when inhibited, cause death of NF2 mutant cells but not NF2 wildtype cells. We thereby identify ACSL3 and G6PD as two synthetic-lethal partners for NF2. We find that NF2 mutant Schwann cells are vulnerable to G6PD inhibition because they have low levels of ME1. G6PD and ME1 redundantly generate cytosolic NADPH needed by cells to fight oxidative stress. Lack of either one of the two is compatible with cell viability, but down-regulation of both leads to Schwann cell death. Since genetic deficiency for G6PD is tolerated in the human population, this raises the possibility that G6PD could be a pharmacological target for NFII.

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G6PD and ACSL3 are synthetic lethal partners of NF2 in Schwann cells

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