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RNA-seq to investigate impact of treatment of KRAS mutant NCI-H2009 lung adenocarcinoma cells with the multi-ERBB inhibitor Neratinib

ABSTRACT: KRAS mutation is widely presumed to confer independence from upstream RTK signalling, however emerging evidence from mouse models of lung cancer suggests that ERBB RTKs may amplify signalling through RAS isoforms and participate in mutant RAS-driven lung cancer. This is one of 3 datasets where we examined the transcriptional impact of treatment of KRAS mutant human lung cancer cell lines with the multi-ERBB inhibitor Neratinib

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Homo sapiens

SUBMITTER: Daniel Murphy

PROVIDER: E-MTAB-6486 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The ERBB network facilitates KRAS-driven lung tumorigenesis.

Kruspig Björn B Monteverde Tiziana T Neidler Sarah S Hock Andreas A Kerr Emma E Nixon Colin C Clark William W Hedley Ann A Laing Sarah S Coffelt Seth B SB Le Quesne John J Dick Craig C Vousden Karen H KH Martins Carla P CP Murphy Daniel J DJ

Science translational medicine 20180601 446

KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are ...[more]

PMID: 29925636

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RNA-seq to investigate impact of treatment of KRAS mutant A549 lung adenocarcinoma cells with the multi-ERBB inhibitor Neratinib

Project description:KRAS mutation is widely presumed to confer independence from upstream RTK signalling, however emerging evidence from mouse models of lung cancer suggests that ERBB RTKs may amplify signalling through RAS isoforms and participate in mutant RAS-driven lung cancer. This is one of 3 datasets where we examined the transcriptional impact of treatment of KRAS mutant human lung cancer cell lines with the multi-ERBB inhibitor Neratinib

2018-06-01 | E-MTAB-6483 | biostudies-arrayexpress

RNA-seq to investigate impact of treatment of KRAS mutant NCI-H358 lung adenocarcinoma cells with the multi-ERBB inhibitor Neratinib

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Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.

2023-06-09 | GSE234449 | GEO

Comparison of KrasG12D/WT;p53Fx/Fx and KrasG12D/G12D;p53Fx/Fx MEFs

2016-02-24 | GSE75871 | GEO

KRAS and YAP1 converge to regulate EMT and tumor survival

Project description:Cancer cells that express oncogenic alleles of RAS typically require sustained expression of the mutant allele for survival, but the molecular basis of this oncogene dependency remains incompletely understood. To identify genes that can functionally substitute for oncogenic RAS, we systematically expressed 15,294 open reading frames in a human KRAS-dependent colon cancer cell line engineered to express an inducible KRAS-specific shRNA. We found 147 genes that promoted survival in the setting of KRAS suppression. In this model, the transcriptional co-activator YAP1 rescued cell viability in KRAS-dependent cells upon suppression of KRAS and was required for KRAS-induced cell transformation. Acquired resistance to Kras suppression in a Kras-driven murine lung cancer model also involved increased YAP1 signaling. KRAS and YAP1 converge on the transcription factor FOS and activate a transcriptional program involved in regulating the epithelial-mesenchymal transition (EMT). Together, these findings implicate transcriptional regulation of EMT by YAP1 as a significant component of oncogenic RAS signaling Three biological replicates of primary lung adenocarcinoma cells derived from the Kras Lox-STOP-Lox-G12D;p53flox/flox (KP) mouse lung cancer model into which a doxycycline-inducible shRNA targeting Kras expressed from the 3’UTR of GFP was introduced (KP-KrasA cells) were analyzed at timepoints (days) D0, D4, and D21.

2014-07-27 | E-GEOD-56175 | biostudies-arrayexpress

Comparison of KrasG12D/WT;p53Fx/Fx and KrasG12D/G12D;p53Fx/Fx MEFs

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2016-02-24 | E-GEOD-75871 | biostudies-arrayexpress

PTEN-deficiency in luminal MMTV-ErbB-2 mouse model results in dramatic acceleration in mammary tumorigenesis/metastasis

Project description:Overexpression and/or amplification of the ErbB-2 oncogene, as well as inactivation of the tumor suppressor PTEN, are two important genetic events in human breast carcinogenesis. To address the biological impact of conditional inactivation of PTEN on ErbB-2-induced mammary tumorigenesis, we generated a novel transgenic mouse model that utilizes the MMTV promoter to directly couple expression of activated ErbB-2 and Cre recombinase to the same mammary epithelial cell (MMTV-NIC). Disruption of PTEN in the mammary epithelium of the MMTV-NIC model system dramatically accelerated the formation of multifocal and highly metastatic mammary tumors, which exhibit homogenous pathology. PTEN-deficient/NIC tumorigenesis was associated with an increase in angiogenesis. Moreover, inactivation of PTEN in the MMTV-NIC mouse model resulted in hyperactivation of the PI3K/Akt signalling pathway. However, like the parental strain, tumors obtained from PTEN-deficient/NIC mice displayed histopathological and molecular features of the luminal-like subtype of breast cancer. Taken together, our findings provide important implications in understanding the molecular determinants of mammary tumorigenesis driven by PTEN deficiency and ErbB-2 activation, and could provide a valuable tool for testing the efficacy of therapeutic strategies that target these critical signalling pathways.

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Gene Regulation by microRNA-16 forced expression in ErbB-2 positive murine breast cancer cells.

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2016-05-04 | GSE73900 | GEO

MEK Inhibitor Trametinib combined with RTK Inhibitor Anlotinib in KRAS-Mutant Lung Cancer

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High efficacy of combined MEK Inhibitor Trametinib and RTK Inhibitor Anlotinib Therapy in KRAS-Mutant Lung Cancer

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2024-11-11 | GSE247512 | GEO

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