A targetable epigenetic vulnerability in PI3K/AKT inhibitor resistant cancers
Huang, H.; Wu, D.; Yan, Y.; Wei, T.; Ye, Z.; Xiao, Y.; Pan, Y.; Orme, J. J.; Wang, D.; Wang, L.; Ren, S.
Show abstract
Acquisition of resistance to PI3K/AKT-targeted monotherapy implies the existence of common resistance mechanisms independent of cancer type. Here we demonstrate that PI3K/AKT inhibitors cause glycolytic crisis, acetyl-CoA shortage and a global decrease in histone acetylation. Also, PI3K/AKT inhibitors induce drug resistance by selectively augmenting H3K27 acetylation and binding of CBP/p300 and BRD4 proteins at a subset of growth factor and receptor (GF/R) gene loci. BRD4 occupation at these loci and drug resistant cell growth are vulnerable to both bromodomain and HDAC inhibitors. Little or none occupation of HDAC proteins 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 two viable strategies to overcome PI3K/AKT inhibitor resistance in different cancers.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- G9a Promotes Breast Cancer Recurrence Through Repression of a Pro-inflammatory Program 96%
- Genetic Impairment of Succinate Metabolism Disrupts Bioenergetic Sensing in Adrenal Neuroendocrine Cancer 96%
- BET inhibition induces an anti-apoptotic adaptive response and therapeutic vulnerability to MCL1 inhibitors in breast cancer 95%
Similar papers in this journal
- Co-regulation and functional cooperativity of FOXM1 and RHNO1 bidirectional genes in ovarian cancer 96%
- An epigenetic switch regulates the ontogeny of AXL positive/EGFR-TKI resistant cells by modulating miR-335 expression 96%
- Oncogenic PKA signaling stabilizes MYC oncoproteins via an aurora kinase A-dependent mechanism 96%
Similar papers in this journal
- Glucose deprivation promotes pseudo-hypoxia and de-differentiation in lung adenocarcinoma 96%
- EZH2 synergizes with BRD4-NUT to drive NUT carcinoma growth through silencing of key tumor suppressor genes 95%
- Hypoxia Drives Dihydropyrimidine Dehydrogenase Expression in Macrophages and Confers Chemoresistance in Colorectal Cancer 94%
Similar papers in this journal
- Prolonging lung cancer response to EGFR inhibition by targeting the selective advantage of resistant cells 96%
- Bone morphogenetic protein (BMP) signaling determines neuroblastoma cell fate and sensitivity to retinoic acid. 95%
- H3K27me3 mediated KRT14 upregulation promotes TNBC peritoneal metastasis 95%
Similar papers in this journal
- A Non-genetic Mechanism for Chemoresistance in Lung Cancer: The Role of Integrin β4/Paxillin Axis 96%
- Activation of AKT induces EZH2-mediated beta-catenin trimethylation in colorectal cancer 95%
- NDC80 status pinpoints mitotic kinase inhibitors as emerging therapeutic options in clear cell renal cell carcinoma 94%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.