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Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells

ABSTRACT: Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells

PROVIDER: PRJNA850416 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19737139_1.fastq.gz	Fastqsanger.gz
	SRR19737139_2.fastq.gz	Fastqsanger.gz
	SRR19737140_1.fastq.gz	Fastqsanger.gz
	SRR19737140_2.fastq.gz	Fastqsanger.gz
	SRR19737141_1.fastq.gz	Fastqsanger.gz

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Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells [RNA-seq]

Project description:We report the development of a second-generation AKT degrader INY-05-040, which outperformed catalytic AKT inhibition both with respect to biochemical and cellular suppression of AKT/mTORC1-driven phenotypes in diverse breast cancer cell lines. Using multi-omic profiling and causal network integration, we demonstrate that the enhanced efficacy of INY-05-040 relies in part on potent downstream activation of stress mitogen activated protein kinase (MAPK) signaling. Systematic measurements of growth inhibition across 288 cancer cell lines confirmed the substantial improvement in potency for INY-05-040 compared to the first-generation AKT degrader (INY-03-041) and catalytic AKT inhibition with GDC-0068. Subsequent integration of breast cancer cell line-specific data with publicly available transcriptomic, proteomic and reverse phase protein array (RPPA) measurements revealed that decreased sensitivity to INY-05-040 correlates with a high baseline activation of inflammatory/stress signaling pathways. Collectively, our data uncover a unique mechanism of breast cancer cell line sensitivity to AKT degradation, further suggesting that the efficacy of catalytic AKT inhibition may be enhanced by activation of stress MAPKs in breast cancer cells with low baseline activity of these components.

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Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells [RNA-seq]

Project description:Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells [RNA-seq]

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Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells [PRO-seq]

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Transcriptomic comparison of a second-generation AKT degrader to the catalytic AKT inhibitor GDC0068 in breast cancer cells

Project description:This SuperSeries is composed of the SubSeries listed below.

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Multi-omic profiling of breast cancer cells uncovers stress MAPK-associated sensitivity to AKT degradation

Project description:Over 50% of human tumors display hyperactivation of the serine/threonine kinase AKT, but AKT inhibitors under clinical investigation lack therapeutic efficacy at tolerable doses and display significant on-target toxicities. Here we report the development of a second-generation AKT degrader, INY-05-040, which outperformed catalytic AKT inhibition both with respect to biochemical and cellular suppression of AKT-driven phenotypes in breast cancer cell lines. A systematic growth inhibition screen across 288 cancer cell lines confirmed a substantially higher potency for INY-05-040 (median GI50adj = 1.1 µM) compared to our first-generation AKT degrader (INY-03-041; median GI50adj = 3.1 µM), with both compounds outperforming catalytic AKT inhibition with GDC-0068 (median GI50adj > 10 µM). Using multi-omic profiling and causal network integration in breast cancer cells, we demonstrate that the enhanced efficacy of INY-05-040 is associated with sustained suppression of AKT signaling, followed by a potent induction of the stress mitogen activated protein kinase (MAPK) cJun N-terminal kinase (JNK). Further integration of growth inhibition assays with publicly available transcriptomic, proteomic, and reverse phase protein array (RPPA) measurements established low baseline JNK signaling as a biomarker for breast cancer sensitivity to AKT degradation. Collectively, our study presents a systematic framework for mapping the network-wide signaling effects of therapeutically relevant compounds, revealing that INY-05-040 is a potent pharmacological suppressor of AKT signaling.

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Project description:The PI3K/AKT signaling cascade is one of the most commonly dysregulated pathways in cancer, with over 50% of tumors showing aberrant AKT hyperactivation. Although potent small molecule AKT inhibitors have entered clinical trials, robust and durable therapeutic responses have not been observed. As an alternative strategy to target AKT, we report the development of INY-03-041, a pan-AKT degrader consisting of GDC-0068, an AKT inhibitor, conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase, Cereblon (CRBN). INY-03-041 induced potent degradation of all three AKT isoforms and displayed enhanced anti-proliferative effects relative to GDC-0068. Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 hours, even after compound washout. Overall, our findings suggest that AKT degradation may provide prolonged pharmacological effects compared to inhibition, and highlight the potential advantages of AKT-targeted degradation.

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