An epigenetic vulnerability in PI3K/AKT inhibition resistant cancers is targetable by both bromodomain and HDAC inhibitors
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PROVIDER: PRJNA614914 | ENA |
REPOSITORIES: ENA
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Project description:Acquisition of resistance to PI3K/AKT-targeted monotherapy regardless of cancer types implies the existence of common mechanisms. Here we demonstrate that while causing glycolysis crisis, acetyl-CoA shortage and global decrease of histone acetylation, PI3K/AKT inhibitors induce drug resistance by selectively augmenting CBP/p300, H3K27 acetylation and BRD4 binding at genomic loci of a subset of growth factor and receptor (GF/R) genes. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDACs at the GF/R gene loci underscores the paradox that cells respond equivalently to the two classes of inhibitors with opposite modes of action. Targeting this unique epigenetic vulnerability offers a general solution to overcome PI3K/AKT inhibitor resistance in different cancers.
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Project description:Deregulated oxidative metabolism is a hallmark of leukaemia. While use of tyrosine kinase inhibitors (TKIs) such as imatinib has led to increased survival of chronic myeloid leukaemia (CML) patients, it fails to eradicate disease initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays we generated multi-omics datasets that offer unprecedented insight into nutrient fate in patient derived CML LSCs. We demonstrate that LSCs have increased glucose anaplerosis when compared to normal hematopoietic stem cells. While imatinib treatment reverses BCR-ABL-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics revealed that deregulated glucose anaplerosis is unaffected by imatinib. Encouragingly, genetic ablation of glucose anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that the clinical oral-available inhibitor MSDC-0160 targets glucose anaplerosis in robust pre-clinical CML models. Collectively these results highlight glucose anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient samples.
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Project description:Hyperactivation of the phosphatydil-inositol-3' phosphate kinase (PI3K)/AKT pathway is observed in most NSCLCs, promoting proliferation, migration, invasion and resistance to therapy. AKT can be activated through several mechanisms that include loss of the negative regulator PTEN, activating mutations of the catalytic subunit of PI3K (PIK3CA) and/or mutations of AKT1 itself. However, number and identity of downstream targets of activated PI3K/AKT pathway are poorly defined. To identify the genes that are targets of constitutive PI3K/AKT signalling in lung cancer cells, we performed a comparative transcriptomic analysis of human lung epithelial cells (BEAS-2B) expressing active mutant AKT1 (AKT1-E17K), active mutant PIK3CA (PIK3CA-E545K) or that are silenced for PTEN. For each sample, 500 ng of total RNA were used to synthesize biotinylated cRNA with Illumina RNA Amplification Kit (Ambion, Austin, TX). Synthesis was carried out according to the manufacturersâ instructions. From each sample, technical triplicates were produced and 750 ng cRNA were hybridized for 18h to Human HT-12_V3_0_R1 Expression BeadChips (Illumina, San Diego, CA). Hybridized chips were washed and stained with streptavidin-conjugated Cy3 (GE Healthcare, Milan, Italy). BeadChips were dried and scanned with an Illumina Bead Array Reader (Illumina).
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Project description:Triple-negative breast cancer (TNBC) is responsible for a disproportionate number of breast cancer deaths due to its molecular heterogeneity, high recurrence rate and lack of targeted therapies. Dysregulation of the phosphoinositide 3-kinase (PI3K)/AKT pathway occurs in approximately 50% of TNBC patients. We performed a genome-wide negative selection CRISPR/Cas9 screen with PI3K and AKT inhibitors to identify targetable synthetic lethalities in TNBC. We found that cholesterol homeostasis is a collateral vulnerability with AKT inhibition. Disruption of cholesterol homeostasis with pitavastatin synergized with AKT inhibition to induce TNBC cytotoxicity in vitro, in mouse TNBC xenografts and in patient-derived organoids of estrogen receptor (ER)-negative breast cancer. Neither ER-positive breast cancer cell lines nor ER-positive organoids were sensitive to combined AKT inhibitor and pitavastatin. Mechanistically, TNBCs show dysregulated SREBP-2 activation in response to single agent or combination AKT inhibitor and pitavastatin, and this was rescued by inhibition of the cholesterol trafficking protein Niemann-Pick C1 (NPC1). NPC1 loss promoted lysosomal cholesterol accumulation, decreased endoplasmic reticulum cholesterol levels and promoted SREBP-2 activation. Taken together, these data identify a TNBC-specific vulnerability to the combination of AKT inhibitors and pitavastatin mediated by dysregulated cholesterol trafficking. This work motivates combining AKT inhibitors with pitavastatin as a therapeutic modality in TNBC.
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Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
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2012-07-21 | E-GEOD-35705 | biostudies-arrayexpress