Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE315010 | GEO | 2025/12/29

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental Lu65 cells to those with acquired resistance to RM-4998. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.

Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental H358 cells to those with acquired resistance to the KRAS G12C inhibitor, AMG510. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.

Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental Lu65 cells to those with acquired resistance to the KRAS G12C inhibitor, Sotorasib. Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.

Project description:Small molecule KRASG12C(OFF) inhibitors that bind to the inactive GDP-bound state of KRAS have demonstrated efficacy in patients with KRASG12C mutant tumors, yet responses tend to be transient due to on-treatment resistance. Recently, a RAS(ON) G12C-selective inhibitor, which binds to the active GTP-bound state of KRAS, was introduced into the clinical settings. We generated cell line and PDX resistant models to KRAS G12C(OFF) and RAS(ON) G12C-selective inhibitors that displayed a variety of resistance mechanisms similar to the ones observed in human studies. Here we interrogated resistance mechanisms using a multi-omics strategy consisting of phosphoproteomics, exome sequencing, and RNA-sequencing then coupled these analyses to functional testing using small molecule screens, CRISPR screens and combination with RAS(ON) inhibitors that have entered clinical trials. We found two models that reactivate RAS signaling, either via KRASG12C gene amplification or NRASG13R mutation, and showed that tumors driven by these resistance mechanisms are vulnerable to dual inhibition by either RAS(ON) G12C-selective combined with RAS(ON) multi-selective inhibitor. Two models, which lack any discernable genomic alteration, acquired resistance associated with increased receptor tyrosine kinase activity and downstream persistent RAS activity, were sensitive to RAS-GTP inhibition by RAS(ON) multi-selective inhibitor. Finally, one model displayed epithelial-mesenchymal transition, loss of RAS activity and acquired dependence on cell cycle kinases and proteins associated with DNA damage response. Our work highlights KRASi-resistant states that could potentially be overcome with a RAS(ON) multi-selective inhibitor as a standalone agent or in carefully tailored combinations. It also identifies resistant tumors that have reduced RAS dependance, thereby necessitating alternative therapeutic strategies. These datasets compare parental LUN156 patient-derived xenograft tumors to those with acquired resistance to the KRAS G12C inhibitors, Adagrasib (AR) and RM-4998 (RR). Data are provided for protein expression (ID), global phosphorylation (IMAC), and tyrosine phosphorylation (pY) as indicated in the filenames.

Dataset Information

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

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets