Project description:Reverse Crosslink ControlChIP-seq on human MCF-7 (fragmentation date 03-05-14) For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODE_Data_Use_Policy_for_External_Users_03-07-14.pdf
Project description:H69 cells were cultured in H69 medium with 1 ng/ml lipopolysaccharide(LPS, for smaples 04, 05 and 06) or without LPS(for samples 01, 02 and 03) for 8 hours and then collected for array analysis. <br>
Project description:H69 cells were cultured in H69 medium with Cryptosporidium parvum oocysts(10 X 5 per well, for smaples 04, 05 and 06) or without oocysts(for samples 01, 02 and 03)for 8 hours and then collected for array analysis. Sample 07 was cells exposed to heated inactived oocysts. <br>
Project description:We used next-generation sequencing to identify differential microRNA (miRNA) signatures in exosomes isolated from ovarian cancer cells and ovarian cancer-associated fibroblasts (CAFs) and adipocytes (CAAs). We found that a significantly higher levels of miR21 isomiRNAs in exosomes isolated from CAFs and CAAs than in those from ovarian cancer cells.
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.
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.
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.