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| 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
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| 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.
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| 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.
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| Contributor(s) |
Tiriac H |
| Citation missing |
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| Submission date |
Jun 08, 2023 |
| Last update date |
Jun 24, 2023 |
| Contact name |
Herve Tiriac |
| E-mail(s) |
htiriac@health.ucsd.edu
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| Phone |
8582465564
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| Organization name |
UCSD Health
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| Department |
Surgery
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| Street address |
3855 Health Sciences Drive
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| City |
La Jolla |
| State/province |
CA |
| ZIP/Postal code |
92093 |
| Country |
USA |
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| Platforms (2) |
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| Samples (11)
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| GSM7468769 |
RNAseqofSUIT2PT:untreated (replicate 1) |
| GSM7468770 |
RNAseqofSUIT2PT:60nM MRTX1133 (replicate 1) |
| GSM7468771 |
RNAseqofSUIT2PT:60nM MRTX1133 (replicate 2) |
| GSM7468772 |
RNAseqofSUIT2MRTXR:untreated (replicate 1) |
| GSM7468773 |
RNAseqofSUIT2MRTXR:untreated (replicate 2) |
| GSM7468774 |
RNAseqofSUIT2MRTXR:60nM MRTX1133 (replicate 1) |
| GSM7468775 |
RNAseqofSUIT2MRTXR:60nM MRTX1133 (replicate 2) |
| GSM7468776 |
RNAseq of FC1242 PT (replicate 1) |
| GSM7468777 |
RNAseq of FC1242 PT (replicate 2) |
| GSM7468778 |
RNAseq of FC1242 MRTXR (replicate 1) |
| GSM7468779 |
RNAseq of FC1242 MRTXR (replicate 2) |
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| Relations |
| BioProject |
PRJNA981460 |
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