GEO series

Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-refractory KRASG12C-mutant NSCLC for Immune Checkpoint Blockade

GSE315010 Homo sapiens; Mus musculus Expression profiling by high throughput sequencing 44 samples Submitted 2025/12/29 Platform GPL24247Platform GPL34281

Summary

To address RAS pathway hyperactivation and targeted therapy resistance in KRASG12C-mutant NSCLC, we evaluated the potential of the RAS(ON) G12C-selective covalent inhibitor elironrasib and the RAS(ON) multi-selective inhibitor daraxonrasib combination to maximize RAS pathway suppression and forestall pathway reactivation in a series of preclinical models. We demonstrate that the RAS(ON) inhibitor doublet induces profound and sustained tumor regressions and overcomes the increased RAS pathway oncogenic flux that underlies resistance to inactive state–selective KRASG12C inhibitors in NSCLC. Additionally, in immune-competent preclinical models, the RAS(ON) inhibitor doublet enhances tumor immune recognition by boosting antigen presentation and remodeling the suppressive tumor microenvironment, thus promoting immune-dependent complete regressions and sensitization of an immuno-refractory model to checkpoint blockade. Collectively these findings provide a preclinical rationale for the evaluation of a targeted RAS(ON) inhibitor doublet therapy regimen in combination with immune checkpoint blockade in patients with KRASG12C-mutant NSCLC.

This dataset

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Direct links to NCBI, no account and no request form: the whole study as GSE315010_RAW.tar, processed values as the series matrix, the supplementary file directory, and per-sample supplementary files for any of the 44 samples. Raw sequencing reads are also available from ENA.

Whole study · RAW.tar ↓ Series matrix ↓ All supplementary files ↗ Raw reads on ENA ↗

Also filed as BioProject PRJNA1394784 and SRA study SRP658362. Searching any of these in the dataset finder brings you back here.

NCBI GEO page ↗

Study design

11 conditions, mostly in triplicate

e3LL_vehicle_8day ×5 e3LL_RMC-6291_8day ×5 e3LL_RMC-6236_8day ×5 NCI-H2122_vehicle_24hour ×3 NCI-H2122_vehicle_8hour ×3 NCI-H2122_RMC-6291_24hour ×3 NCI-H2122_RMC-6291_8hour ×3 NCI-H2122_RMC-6236_24hour ×3 +4 more

Supports a between-group comparison across 39 samples.

11 replicated groups read from the first 40 of 44 sample titles; they account for 39 of them. Check it against the sample list below before relying on it.

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