GEO series
Resistance to the KRASG12D Inhibitor MRTX1133 is Associated with Aberrant Histone Acetylation and Increased Sensitivity to BET Inhibition
GSE294216
Homo sapiens; Mus musculus
Expression profiling by high throughput sequencing
36 samples
Submitted 2026/03/23
Platform GPL24247Platform GPL24676
Summary
As many as 90% of human pancreatic ductal adenocarcinoma (PDAC) tumors harbor gain-of-function mutations in the KRAS oncogene. Recently, inhibitors of the most common KRAS mutation, KRASG12D, have entered the clinical arena. However, early evidence suggests that as monotherapy, KRASG12D inhibitors such as MRTX1133 at best provide brief periods of disease stabilization. Hence, there is a growing interest in understanding the mechanisms through which tumors acquire resistance to KRAS inhibition. In the present study, we generated in vitro models of MRTX1133 resistance and subjected parental and drug-resistant cell lines to RNA sequencing. This suggested that MRTX1133-resistant tumor cells undergo a global shift toward histone acetylation. Inhibition of the histone acetyltransferase EP300 reversed the drug-resistant phenotype in vitro, which subsequent RNA sequencing experiments determined was associated with the suppression of pro-survival FOSL1 signaling. Accordingly, siFOSL1 reversed the MRTX1133-resistant phenotype with similar effects on pro-survival signaling. Given the lack of clinically useful EP300 or FOSL1 inhibitors, we next explored whether inhibitors of the acetylation scanning BET proteins would be similarly effective. The addition of BET inhibitors re-sensitized several highly resistant cell lines to MRTX1133 and impaired FOSL1-mediated survival signaling in vitro. In murine models of MRTX1133-resistant PDAC, BET inhibition cooperated with MRTX1133 to markedly extend overall survival. As BET inhibitors are currently under clinical testing, the combination of MRTX1133 and BET inhibitors warrants further investigation, particularly in tumors that have developed resistance to KRAS inhibition.
This dataset
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Direct links to NCBI, no account and no request form: the whole study as GSE294216_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 36 samples. Raw sequencing reads are also available from ENA.
Also filed as BioProject PRJNA1248575 and SRA study SRP577548. Searching any of these in the dataset finder brings you back here.
Study design
12 conditions, mostly in triplicate
PANC1 ×3
PANC1K ×3
2138 ×3
2138K ×3
PANC1K DMSO ×3
PANC1K SGC ×3
PANC1K JQ1 ×3
PANC1K OTX ×3
+4 more
Supports a between-group comparison across 36 samples.
12 replicated groups read from 36 sample titles; they account for 36 of them. Check it against the sample list below before relying on it.
Samples in this study
0 selected
- GSM8900442 PANC1-1
- GSM8900443 PANC1-2
- GSM8900444 PANC1-3
- GSM8900445 PANC1K-1
- GSM8900446 PANC1K-2
- GSM8900447 PANC1K-3
- GSM8900448 2138-1
- GSM8900449 2138-2
- GSM8900450 2138-3
- GSM8900451 2138K-1
- GSM8900452 2138K-2
- GSM8900453 2138K-3
- GSM8900454 PANC1K DMSO-1
- GSM8900455 PANC1K DMSO-2
- GSM8900456 PANC1K DMSO-3
- GSM8900457 PANC1K SGC-1
- GSM8900458 PANC1K SGC-2
- GSM8900459 PANC1K SGC-3
- GSM8900460 PANC1K JQ1-1
- GSM8900461 PANC1K JQ1-2
- GSM8900462 PANC1K JQ1-3
- GSM8900463 PANC1K OTX-1
- GSM8900464 PANC1K OTX-2
- GSM8900465 PANC1K OTX-3
- GSM8900466 PANC1K siControl-1
- GSM8900467 PANC1K siControl-2
- GSM8900468 PANC1K siControl-3
- GSM8900469 PANC1K siFOSL1-1
- GSM8900470 PANC1K siFOSL1-2
- GSM8900471 PANC1K siFOSL1-3
- GSM8900472 2138K DMSO-1
- GSM8900473 2138K DMSO-2
- GSM8900474 2138K DMSO-3
- GSM8900475 2138K SGC-1
- GSM8900476 2138K SGC-2
- GSM8900477 2138K SGC-3
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