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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 |
| Organisms |
Homo sapiens; 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 |
RNA-seq of MRTX1133-resistant human and murine cell lines were generated from parental cell lines by continuous dose escalation from as low as 1nM to 10μM. Once resistance to MRTX1133 was confirmed, resistant cell lines were routinely maintained in the corresponding medium with 1uM (10% of the maximum dose reached during the evolution of resistance) of MRTX1133.
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| Contributor(s) |
Dilly J, Aguirre A |
| Citation(s) |
38975874 |
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| Submission date |
Jun 16, 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 (2) |
| GPL24247 |
Illumina NovaSeq 6000 (Mus musculus) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (30)
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| GSM8332068 |
Panc 02.03 MRTX1133 resistant, replicate 1 |
| GSM8332069 |
Panc 02.03 MRTX1133 resistant, replicate 2 |
| GSM8332070 |
Panc 02 03 MRTX1133 resistant, replicate 3 |
| GSM8332071 |
PANC-1 parental replicate 1 |
| GSM8332072 |
PANC-1 parental replicate 2 |
| GSM8332073 |
PANC-1 parental replicate 3 |
| GSM8332074 |
PANC-1 MRTX1133 resistant, replicate 1 |
| GSM8332075 |
PANC-1 MRTX1133 resistant, replicate 2 |
| GSM8332076 |
PANC-1 MRTX1133 resistant, replicate 3 |
| GSM8332077 |
6694C2 parental replicate 1 |
| GSM8332078 |
6694C2 parental replicate 2 |
| GSM8332079 |
6694C2 parental replicate 3 |
| GSM8332080 |
6694C2 MRTX1133 resistant, replicate 1 |
| GSM8332081 |
6694C2 MRTX1133 resistant, replicate 2 |
| GSM8332082 |
6694C2 MRTX1133 resistant, replicate 3 |
| GSM8332083 |
6499C4 parental replicate 1 |
| GSM8332084 |
6499C4 parental replicate 2 |
| GSM8332085 |
6499C4 parental replicate 3 |
| GSM8332086 |
6499C4 MRTX1133 resistant, replicate 1 |
| GSM8332087 |
6499C4 MRTX1133 resistant, replicate 2 |
| GSM8332088 |
6499C4 MRTX1133 resistant, replicate 3 |
| GSM8332089 |
6419C5 parental replicate 1 |
| GSM8332090 |
6419C5 parental replicate 2 |
| GSM8332091 |
6419C5 parental replicate 3 |
| GSM8332092 |
6419C5 MRTX1133 resistant, replicate 1 |
| GSM8332093 |
6419C5 MRTX1133 resistant, replicate 2 |
| GSM8332094 |
6419C5 MRTX1133 resistant, replicate 3 |
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| Relations |
| BioProject |
PRJNA1124557 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE269985_RAW.tar |
12.8 Mb |
(http)(custom) |
TAR (of CSV) |
SRA Run Selector |
| Raw data are available in SRA |
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