Transcriptional landscape of oncogenic PI3K
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus Homo sapiens
PROVIDER: GSE157858 | GEO | 2022/04/25
REPOSITORIES: GEO
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Project description:PIK3CA is the second most mutated gene in cancer leading to aberrant PI3K/AKT/mTOR signaling and increased translation, proliferation, and survival. Some 4-25% of gastric cancers display activating PIK3CA mutations including 80% of EBV-associated GCs. Small molecules including pan-PI3K and dual PI3K/mTOR inhibitors have shown moderate success clinically, due to broad on-target/off-tissue effects. Thus, isoform specific and mutant selective inhibitors have been of significant interest. However, drug resistance is a problem and has affected success of new drugs. There has been a concerted effort to define mechanisms of resistance and identify potent combinations in many tumor types, though gastric cancer is comparatively understudied. In this study we identified modulators of the response to the PI3Ka-specific inhibitor, BYL719, in PIK3CA mutant GCs. We found that loss of NEDD9 or inhibition of BCL-XL conferred hyper-sensitivity to BYL719, through increased cell cycle arrest and cell death, respectively. Additionally, we discovered that loss of CBFB conferred resistance to BYL719. CBFB loss led to up-regulation of the protein kinase PIM1, which can phosphorylate and activate several overlapping downstream substrates as AKT thereby maintaining pathway activity in the presence of PI3Ka inhibition. The addition of a pan-PIM inhibitor re-sensitized resistant cells to BYL719. Our data provide clear mechanistic insights into PI3Ka inhibitor response in PIK3CA mutant gastric tumors and can inform future work as mutant selective inhibitors are in development for diverse tumor types.
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Project description:The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents a rational target for therapeutic intervention. In order to investigate the primary phenotype(s) mediated by mutant PIK3CA in a clean and highly patient-relevant context, we utilized a non-tumorigenic MCF10A parental and isogenic knock-in cell line that harbors a common activating PIK3CA kinase domain mutation (H1047R). We found that introduction of an endogenously mutated PIK3CA primarily results in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype compared to isogenic wild-type cells. Moreover, a potent and selective inhibitor of PIK3CA (GDC-0941) was highly effective and selective on reversing this phenotype compared to cell-proliferation, highlighting a potential new paradigm for studying PI3K-pathway targeted agents. Keywords: Expression Array Gene expression profiles from a parental MCF10A breast line and an MCF10A clone that has a PI3K activating mutation (H1047R) knocked-in. We plated the cells in 10cm dishes overnight in media with serum, but lacking EGF or insulin. DMSO or GDC-0941 (PI3K inhibitor) at an EC50 concentration were added to triplicate plates of cells in the morning. After 4 hours the RNA was harvested using the Qiagen RNeasy kit. There are 12 samples total.
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Project description:Wild-type and PIK3CA mutant MCF10A cell lines were analyzed using shotgun proteomics to identify proteins that were altered by either 545K or H1047R PIK3CA mutations. Cell lines were digested and fractionated using isoelectric focusing and peptides were analyzed using LC-MS/MS analysis.
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Project description:This study examined the effect of mutant PIK3CAH1047R expression in mammary subsets of preneoplastic mammary glands from Lgr5-creERT2/PIK3CA H1047R mice Mammary cell subpopulations were isolated from Lgr5-creERT2/PIK3CA H1047R and Lgr5-creERT2 control animals 4 weeks after activation of PIK3CA H1047R transgene expression by Tamoxifen injection. Pooled mammary glands of 2-3 estrus-synchronized mice per genotype were sorted in 3 independent sortings and used for microarray analysis (24 samples in total).
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