GEO Logo
   NCBI > GEO > Accession DisplayHelp Not logged in | LoginHelp
GEO help: Mouse over screen elements for information.
Series GSE235631 Query DataSets for GSE235631
Status Public on Jun 30, 2023
Title CBF-beta mitigates PI3K-alpha specific inhibitor killing through PIM1 in PIK3CA mutant gastric cancer
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design To determine the mechanism of PI3Ka inhibitor resistance in PIK3CA mutant gastric cancer cells, we generated AGS cell lines with developed resistance to BYL719. We additionally generated AGS cells with genetic knockout of CBFB. We then performed gene expression profiling analysis using data obtained from RNA-seq of WT, CBFB KO, and BYL719-resistant cell lines basally and following 24 hour acute treatment with 1 uM BYL719.
Contributor(s) Stanland L, Luftig M
Citation missing Has this study been published? Please login to update or notify GEO.
Submission date Jun 22, 2023
Last update date Jun 30, 2023
Contact name Micah Luftig
Organization name Duke University
Street address 213 Research Dr, 0045 CARL
City Durham
State/province North Carolina
ZIP/Postal code 27710
Country USA
Platforms (1)
GPL24676 Illumina NovaSeq 6000 (Homo sapiens)
Samples (20)
GSM7506599 AGS cells, untreated, Biol Rep 1
GSM7506600 AGS cells, untreated, Biol Rep 2
GSM7506601 AGS cells, untreated, Biol Rep 3
BioProject PRJNA986582

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE235631_BYL_BYL719_RvsBYL_WT_deg.xls.gz 3.8 Mb (ftp)(http) XLS
GSE235631_BYL_BYL719_RvsUT_BYL719_R_deg.xls.gz 3.7 Mb (ftp)(http) XLS
GSE235631_BYL_CBFB_KOvsBYL_BYL719_R_deg.xls.gz 4.2 Mb (ftp)(http) XLS
GSE235631_BYL_CBFB_KOvsBYL_WT_deg.xls.gz 4.2 Mb (ftp)(http) XLS
GSE235631_BYL_CBFB_KOvsUT_CBFB_KO_deg.xls.gz 4.5 Mb (ftp)(http) XLS
GSE235631_BYL_WTvsUT_WT_deg.xls.gz 3.8 Mb (ftp)(http) XLS
GSE235631_UT_BYL719_RvsUT_WT_deg.xls.gz 3.8 Mb (ftp)(http) XLS
GSE235631_UT_CBFB_KOvsUT_BYL719_R_deg.xls.gz 4.2 Mb (ftp)(http) XLS
GSE235631_UT_CBFB_KOvsUT_WT_deg.xls.gz 4.2 Mb (ftp)(http) XLS
SRA Run SelectorHelp
Raw data are available in SRA
Processed data are available on Series record

| NLM | NIH | GEO Help | Disclaimer | Accessibility |
NCBI Home NCBI Search NCBI SiteMap