Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Integrative analysis of intrinsic and adaptive resistance to KRASG12C inhibitors in lung adenocarcinoma models

ABSTRACT: KRASG12C inhibitors have been widely reported and studied in recent years. Some of the inhibitors, such as AMG510 and ARS1620, have been reported in clinical studies to be effective in treating patients with non-small cell lung cancer (NSCLC). However, the rapid development of drug resistance in tumor cells will delay the clinical application of these drugs. Therefore, how to block the resistance to these inhibitors in tumor cells with KRASG12C mutations is crucial. We report the alteration in transcriptomics of NSCLC cell line H358 after long-term ARS1620 treatment to explore the mechanism of H358 resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE164326 | GEO | 2021/01/06

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

KRAS inhibitor-resistance in MET-amplified KRASG12C 1 non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanism

Project description:Treatment with KRASG12C inhibitors such as sotorasib can produce substantial regression of tumors in some patients with non-small cell lung cancer (NSCLC). These patients require alternative treatment after acquiring resistance to the inhibitor. The mechanisms underlying this acquired resistance are unclear. The purpose of this study was to identify the mechanisms underlying acquired sotorasib resistance, and to explore potential treatments for rescuing patients with sotorasib-resistant KRASG12C NSCLC cells.

2021-08-01 | GSE179212 | GEO

EVALUATION OF KRASG12C INHIBITOR RESPONSES IN NOVEL MURINE KRASG12C LUNG CANCER CELL LINE MODELS

Project description:The KRAS(G12C) mutation is the most common genetic mutation in North American lung adenocarcinoma patients. Recently, direct inhibitors of the KRASG12C protein have been developed and demonstrate clinical response rates of 37-43%. Importantly, these agents fail to generate durable therapeutic responses with median progression-free survival of ~6.5 months. To provide models for further preclinical improvement of these inhibitors, we generated three novel murine KRASG12C-driven lung cancer cell lines. The co-occurring NRASQ61L mutation in KRASG12C-positive LLC cells was deleted and the KRASG12V allele in CMT167 cells was edited to KRASG12C with CRISPR/Cas9 methods. Also, a novel murine KRASG12C line, mKRC.1, was established from a tumor generated in a genetically-engineered mouse model. The three lines exhibit similar in vitro sensitivities to KRASG12C inhibitors (MRTX-1257, AMG-510), but distinct in vivo responses to MRTX-849 ranging from progressive growth with orthotopic LLC-NRAS KO tumors to marked shrinkage with mKRC.1 tumors. All three cell lines exhibited synergistic in vitro growth inhibition with MRTX-1257 and the SHP2 inhibitor, RMC-4550 and the MRTX-849/RMC-4550 combination yielded tumor shrinkage in orthotopic LLC-NRAS KO tumors propagated in syngeneic mice. Notably, this synergistic combination response was lost in athymic nu/nu mice, supporting a growing literature demonstrating a role for adaptive immunity in the response to this class of drugs. These new models of murine KRASG12C mutant lung cancer should prove valuable for identifying improved therapeutic combination strategies with KRASG12C inhibitors.

2022-07-01 | GSE207098 | GEO

Expression data from tumor lungs after continuous vs. pulsatile selumetinib treatment in KRASG12C GEMM

Project description:KRAS is one of the driver oncogenes in non-small cell lung cancer (NSCLC), but remains refractory to current modalities of targeted pathway inhibition, which include inhibiting downstream kinase MEK to circumvent KRAS activation. Here, we show that pulsatile, rather than continuous, treatment with MEK inhibitors (MEKis) maintains T cell activation and better control tumor growth and survival. We used microarrays to examine the MAPK signaling pathway suppression from tumor lungs of KRASG12C GEMM after continuous vs. pulsatile treatment of selumetinib.

2019-09-11 | GSE126202 | GEO

Integrative analysis of intrinsic and adaptive resistance to KRASG12C inhibitors in lung adenocarcinoma models

Project description:Integrative analysis of intrinsic and adaptive resistance to KRASG12C inhibitors in lung adenocarcinoma models

| PRJNA689906 | ENA

Targeting Focal Adhesion Kinase overcomes erlotinib resistance in smoke induced lung cancer by altering phosphorylation of Epidermal Growth Factor Receptor

Project description:Cigarette smoking is the leading cause for non-small cell lung carcinoma (NSCLC). Tyrosine kinase inhibitors (TKIs) targeting EGFR are in clinical practice and has benefitted patients with EGFR mutations. However, EGFR based targeted therapies have shown limited success in smokers. Identification of alternate signaling mechanism(s) leading to TKI resistance in smokers is critical for developing novel therapies for lung cancer. We observed increased resistance to erlotinib in H358 lung cancer cells exposed to cigarette smoke (H358-S) compared to parental cells. To systematically identify signaling pathways that could potentially confer resistance to erlotinib, we carried out stable isotope labeling by amino acids in cell culture (SILAC)-based phosphotyrosine analysis of H358-S and parental cells. We identified 238 unique phosphosites, of which 111 phosphosites were hyperphosphorylated (≥ 2-fold¬¬¬¬¬¬) in H358 -S cells. Importantly, we observed hyperphosphorylation of EGFR at Y1197 and non-receptor tyrosine kinases, including FAK and FRK in H358-S cells. Inhibition of FAK with its inhibitor PF-562271 led to decreased cellular proliferation and invasive ability of the smoke exposed cells. Further, we observed that treatment with PF-562271 could restore dependency of H358-S cells on EGFR signaling.

2018-03-21 | PXD006705 | Pride

KRASG12C inhibition produces a driver-limited state revealing collateral dependencies

Project description:Inhibitors targeting KRASG12C, a mutant form of the guanosine triphosphatase (GTPase) KRAS, are a promising new class of oncogene-specific therapeutics for the treatment of tumors driven by the mutant protein. These molecules react with the mutant cysteine residue by binding covalently to the switch-II pocket (S-IIP) that is present only in the inactive guanosine diphosphate (GDP)-bound state of KRASG12C, sparing the wild-type protein. We used a genome-scale CRISPR interference (CRISPRi) functional genomics platform to systematically identify genetic interactions with the KRASG12C inhibitor in cellular models of KRASG12C mutant lung and pancreatic cancer. Our data revealed genes that were selectively essential in this oncogenic driver-limited cell state, meaning their loss enhanced cellular susceptibility to direct KRASG12C inhibition. We termed such genes “collateral dependencies” (CDs), and identified two classes of combination therapies targeting these CDs that increased KRASG12C target engagement or blocked residual survival pathways in cells and in vivo. From our findings, we also propose a new framework for assessing genetic dependencies with driver oncogenes.

2019-05-03 | GSE130616 | GEO

Cellular States Dictate Adaptive Signaling Responses to KRASG12C Inhibition: Tyrosine Phosphorylation

Project description:Covalent inhibitors of KRASG12C (KRASi) hold considerable progress for tumors driven by this oncogene yet early studies suggest rapid mechanisms of adaptive resistance that appear cell type dependent. To address these challenges, we performed mass spsectrometry baesd phosphoproteomics analysis in KRASG12C cell lines after short term treatment with ARS-1620 and compared phosphoproteomes of KRASG12C cells to understand signaling diversity. Our analysis suggests individual KRASG12C cells responds uniquely to perturbation of KRASG12C. Cell line models can be categorized in epithelial or mesenchymal subtypes and a similar pattern was observed in KRASG12C human lung cancer tumor tissues. ERBB2/3 signaling compensate for repressed ERK signaling following ARS-1620 treatment in epithelial cell type, and this subtype was also more responsive to inhibition of SHP2, IGFR, and SOS1. Conversely, FGFR signaling drives resistance to KRASi in mesenchymal cells in part via mTOR signaling. These studies suggest transcriptional subtypes of KRASG12C dictate responsiveness to specific combinations.

2021-02-15 | PXD021604 | Pride

Cellular States Dictate Adaptive Signaling Responses to KRASG12C Inhibition: Protein Expression

2021-02-15 | PXD021603 | Pride

Cellular States Dictate Adaptive Signaling Responses to KRASG12C Inhibition: Calu-1 Drug Response Phosphoproteomics

Project description:therapy, drug resistance, signal transduction Covalent inhibitors of KRASG12C (KRASi) hold considerable progress for tumors driven by this oncogene yet early studies suggest rapid mechanisms of adaptive resistance that appear cell type dependent. To address these challenges, we performed mass spsectrometry baesd phosphoproteomics analysis in KRASG12C cell lines after short term treatment with ARS-1620 and compared phosphoproteomes of KRASG12C cells to understand signaling diversity. Our analysis suggests individual KRASG12C cells responds uniquely to perturbation of KRASG12C. Cell line models can be categorized in epithelial or mesenchymal subtypes and a similar pattern was observed in KRASG12C human lung cancer tumor tissues. ERBB2/3 signaling compensate for repressed ERK signaling following ARS-1620 treatment in epithelial cell type, and this subtype was also more responsive to inhibition of SHP2, IGFR, and SOS1. Conversely, FGFR signaling drives resistance to KRASi in mesenchymal cells in part via mTOR signaling. These studies suggest transcriptional subtypes of KRASG12C dictate responsiveness to specific combinations.

2021-02-15 | PXD021608 | Pride

Cellular States Dictate Adaptive Signaling Responses to KRASG12C Inhibition: H358 Drug Response Phosphoproteomics

2021-02-15 | PXD021611 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data