ArticleJournal of experimental & clinical cancer research : CR2026
CRISPR knockout screens reveal JUN as the master mediator of resistance to MAPK inhibition in KRAS-mutant pancreatic cancer.
Article in Journal of experimental & clinical cancer research : CR, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04916236 (Phase I/Ib Study With the Combination of RMC-4630), which is not on this map. Cited by 3 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Phase I/Ib Study With the Combination of RMC-4630 (SHP2 Inhibitor) and LY3214996 (ERK Inhibitor) in Metastatic KRAS Mutant CRC, PDAC and NSCLC
Who cites it
3 citing papers in PubMed.
- High-Content CRISPR Screening: Methods and Applications.MedComm · 2026Review
- Targeted therapeutic strategies forTranslational lung cancer research · 2026Review
- Bracing for the storm: emerging resistance mechanisms to KRAS inhibitors in pancreatic cancer and strategies to overcome them.Cancer drug resistance (Alhambra, Calif.) · 2026Review
Corrections and comments
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Authors and funding
11 authors.
Funding
Abstract
backgroundPancreatic ductal adenocarcinoma (PDAC) is often driven by KRAS mutations, but inhibitors targeting the most frequent KRAS substitutions in PDAC are not yet approved in the clinic. We previously discovered that KRAS-mutant PDAC is sensitive to the combination of SHP2 and ERK inhibitors, recently investigated in the Phase I/Ib clinical trial NCT04916236. Lately, RAS(ON) multi-selective inhibitors have entered clinical development, representing a promise for mono or combination therapies in PDAC. However, resistance may arise even for combination therapies. Here, we aimed at anticipating mechanisms of resistance to SHP2 plus ERK or RAS(ON) multi-selective inhibitors.
methodsWe performed a genome-wide CRISPR-KO screening, followed by four follow-up focused screenings, leading to the identification of resistance mediators, which were further validated through functional genetic and pharmacological experiments, both in vitro and in vivo.
resultsThrough unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression. Further investigation pointed at JUN as the most downstream resistance mediator, and indirect therapeutic target, using MAP2K4 inhibitors.
conclusionsAlterations in the PI3K/AKT/mTOR and JUN pathways can induce resistance to multiple combinations of MAPK pathway inhibitors, and may serve as biomarkers for sensitivity/resistance in clinical trials exploring such combinations in KRAS-mutant PDAC.
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Registered trials
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