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

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Unraveling the CDK9/PP2A/ERK network in transcriptional pause release and complement activation in KRAS-mutant cancers (MIA PaCa-2 )

Project description:KRASG12C inhibitors (KRASG12Ci) AMG510 and MRTX849 have shown promising efficacy in clinical trials and been approved for the treatment of KRASG12C-mutant cancers. However, the emergence of therapy-related drug resistance limits their long-term potential. We measured gene expression using RNA-sequencing for pancreatic cancer cell line MIA PaCa-2 parental and their AMG510-resistant equivalent without treatment or treated with with G12C KRAS inhibitor AMG510.

2024-08-31 | GSE270796 | GEO

CRISPR-screening identifies mechanisms of resistance to KRASG12C and SHP2 inhibitor combinations in non-small cell lung cancer

Project description:Although KRASG12C inhibitors show clinical activity in patients with KRAS G12C mutated NSCLC and other solid tumor malignancies, response is limited by multiple mechanisms of resistance. The KRASG12C inhibitor JDQ443 shows enhanced preclinical antitumor activity combined with the SHP2 inhibitor TNO155, and the combination is currently under clinical evaluation. To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition.

2024-11-01 | GSE246804 | GEO

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

Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C

Project description:Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form of the protein. This suboptimal mechanism provides no direct target coverage against KRASG12C(ON). Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor activated states where current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of downstream signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C (OFF)-only inhibitors.

2024-10-02 | GSE278656 | GEO

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

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

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