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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Jun 17, 2024 |
| Title |
Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.
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| Overall design |
Autochthonous KPC (KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre) genetically engineered mouse model (GEMM) of PDAC were treated with MRTX1133 (KRAS p.G12D inhibitor) or vehicle. Tumors were harvested after 3 days of continuous treatement ("Early vehicle" and “Early MRTX1133”) or after mice reached a humane endpoint ("Endpoint vehicle" or “MRTX1133 resistant”) based on criteria from the Institutional Animal Care & Use Committee (IACUC) at Dana-Farber Cancer Institute (DFCI).
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| Contributor(s) |
Dilly J, Aguirre AJ |
| Citation(s) |
38975874 |
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| Submission date |
Jun 07, 2024 |
| Last update date |
Aug 25, 2024 |
| Contact name |
Julien Dilly |
| E-mail(s) |
julien_dilly@dfci.harvard.edu
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| Phone |
6174167457
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| Organization name |
Dana-Farber Cancer Institute
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| Department |
Medical Oncology
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| Lab |
Aguirre
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| Street address |
450 Brookline avenue
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
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| Platforms (1) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
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| Samples (17)
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| GSM8312884 |
KPC_3421L, MRTX1133 resistant, snRNAseq |
| GSM8312885 |
KPC_3421S, MRTX1133 resistant, snRNAseq |
| GSM8312886 |
KPC_3422, Vehicle, snRNAseq |
| GSM8312887 |
KPC_3441, MRTX1133 resistant, snRNAseq |
| GSM8312888 |
KPC_3518, Vehicle, snRNAseq |
| GSM8312889 |
KPC_3587, Vehicle, snRNAseq |
| GSM8312890 |
KPC_3600, MRTX1133 resistant, snRNAseq |
| GSM8312891 |
KPC_3716, Vehicle, snRNAseq |
| GSM8312892 |
KPC_3767, Early MRTX1133, snRNAseq |
| GSM8312893 |
KPC_3777, Early MRTX1133, snRNAseq |
| GSM8312894 |
KPC_3917, Early MRTX1133, snRNAseq |
| GSM8312895 |
KPC_3920, Early Vehicle, snRNAseq |
| GSM8312896 |
KPC_3947, Early Vehicle, snRNAseq |
| GSM8312897 |
KPC_3975, Early Vehicle, snRNAseq |
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| Relations |
| BioProject |
PRJNA1121188 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE269313_RAW.tar |
2.0 Gb |
(http)(custom) |
TAR (of RDS) |
SRA Run Selector |
| Raw data are available in SRA |
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