Integrative analysis of intrinsic and adaptive resistance to KRASG12C inhibitors in lung adenocarcinoma models
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ABSTRACT:
PROVIDER: PRJNA689906 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13364226.fastq.gz | Fastqsanger.gz | |||
| SRR13364227.fastq.gz | Fastqsanger.gz | |||
| SRR13364228.fastq.gz | Fastqsanger.gz | |||
| SRR13364229.fastq.gz | Fastqsanger.gz | |||
| SRR13364230.fastq.gz | Fastqsanger.gz |
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Project description: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.
2021-01-06 | GSE164326 | GEO
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
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 | PXD021603 | Pride
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 | PXD021609 | Pride
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 | PXD021607 | Pride
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 | PXD021611 | Pride
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
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
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
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