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Series GSE234449 Query DataSets for GSE234449
Status Public on Jun 09, 2023
Title Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma
Organisms Homo sapiens; Mus musculus
Experiment type Expression profiling by high throughput sequencing
Summary Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.
Overall design We analyzed the effect of a KRAS inhibitor (MRTX1133) on pancreatic cancer cells (SUIT2 human pancreatic cancer cell and FC1242 mouse pancreatic cancer cell). Cells were treated with MRTX1133 acutely or chronically and whole RNA was extracted and sequenced.
Contributor(s) Tiriac H
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Submission date Jun 08, 2023
Last update date Jun 24, 2023
Contact name Herve Tiriac
Phone 8582465564
Organization name UCSD Health
Department Surgery
Street address 3855 Health Sciences Drive
City La Jolla
State/province CA
ZIP/Postal code 92093
Country USA
Platforms (2)
GPL20795 HiSeq X Ten (Homo sapiens)
GPL21273 HiSeq X Ten (Mus musculus)
Samples (11)
GSM7468769 RNAseqofSUIT2PT:untreated (replicate 1)
GSM7468770 RNAseqofSUIT2PT:60nM MRTX1133 (replicate 1)
GSM7468771 RNAseqofSUIT2PT:60nM MRTX1133 (replicate 2)
BioProject PRJNA981460

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Supplementary file Size Download File type/resource
GSE234449_FC1242_RNAseq.txt.gz 300.8 Kb (ftp)(http) TXT
GSE234449_SUIT2_RNAseq.txt.gz 543.7 Kb (ftp)(http) TXT
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Processed data are available on Series record

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