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RNA-seq to investigate impact of treatment of KRAS mutant NCI-H358 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-6485 | 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

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

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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

Project description:Oncogenic KRAS mutations frequently detected in non-small cell lung cancer (NSCLC)1,2, have been considered undruggable until recent development of inhibitors, e.g., sortorasib, adagrasib or divarasib, specifically targeting KRASG12C 3-6. However, it still remains as a big challenge to target all the KRAS mutants besides KRASG12C 2,7,8. We here found that MEK inhibitor trametinib treatment results in the feedback activation of multiple receptor tyrosine kinases (RTKs) in NSCLC, and combined treatments with trametinib and anlotinib, a pan-RTK inhibitor, effectively inhibited KRAS-mutant lung cancer progression.

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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.

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

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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

Project description:Microarray expression data generated to compare the biological impact of KrasG12D allelic duplication in p53null mouse embryonic fibroblasts (MEFs). The RAS/MAPK-signalling pathway is frequently deregulated in non-small cell lung cancer (NSCLC), often through activating mutations in KRAS. Mouse models demonstrated that activation of a single endogenous mutant Kras allele is sufficient to promote lung tumour formation, but acquisition of other genetic alterations is required for malignant progression. Using a well-established lung cancer mouse model we recently demonstrated that advanced KrasG12D-driven spontaneous tumours frequently exhibit enhanced MAPK signalling and KrasG12D allelic enrichment (KrasG12D/Kraswild-type>1), implying that mutant Kras copy gains are positively selected during lung cancer progression. To compare the oncogenic impact of a single mutant allele versus additional mutant Kras copy gain, we carried out a comprehensive analysis of mutant Kras homozygous and heterozygous MEFs and lung cancer cells and show that these genotypes are phenotypically distinct. Title: Mutant Kras copy number defines metabolic reprogramming and therapeutic susceptibilities Authors: Emma M Kerr, Edoardo Gaude, Frances K Turrell, Christian Frezza and Carla P Martins For MEF generation, KrasLSL-G12D/+ ;p53Fx/Fx mixed background (C57Bl/6/129/Sv) animals were interbred and embryos collected at day E12.5 to overcome KrasLSL-G12D/G12D embryonic lethality and Cre-mediated recombination performed immediately after MEF generation. Cells were cultured in DMEM supplemented with 10% FBS, 2 mM L-Glutamine for one passage and then infected with adenovirus-Cre (5âÃâ107âplaque-forming units/1 x 106 cells). Recombination of LoxP sites was confirmed by PCR analysis. Three independent embryos per genotype were analysed using GPL6887 Illumina MouseWG-6 v2.0 expression beadchip.

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

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