Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo
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PROVIDER: PRJNA695806 | ENA |
REPOSITORIES: ENA
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Project description:Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo
| PRJNA610845 | ENA
Project description:Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo
| PRJNA695807 | ENA
Project description:Cancer genome sequencing has uncovered substantial complexity in the mutational landscape of tumors. Given this complexity, experimental approaches are necessary to establish the impact of combinations of genetic alterations on tumor biology and to uncover genotype-dependent effects on drug sensitivity. In lung adenocarcinoma, EGFR mutations co-occur with many putative tumor suppressor gene alterations, however the extent to which these alterations contribute to tumor growth and their response to therapy in vivo has not been explored experimentally. By integrating a novel mouse model of oncogenic EGFR-driven Trp53-deficient lung adenocarcinoma with multiplexed CRISPR–Cas9-mediated genome editing and tumor barcode sequencing, we quantified the effects of inactivation of ten putative tumor suppressor genes. Inactivation of Apc, Rb1, or Rbm10 most strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 – which were the strongest drivers of tumor growth in an oncogenic Kras-driven model – reduced EGFR-driven tumors growth. These results were consistent with the relative frequency of these tumor suppressor gene alterations in human EGFR and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduced the sensitivity of tumors to osimertinib in the EGFRL858R;p53flox/flox model. Importantly, in human EGFR/TP53 mutant lung adenocarcinomas, mutations in the KEAP1 pathway correlated with decreased time on tyrosine kinase inhibitor treatment. Our study highlights how genetic alterations can have dramatically different biological consequences depending on the oncogenic context and that the fitness landscape can shift upon drug treatment.
2021-02-01 | GSE146550 | GEO
Project description:In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations; however, the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating 10 putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2-the strongest drivers of growth in a KRAS-driven model-reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, KEAP1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib, and mutations in genes in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differs across oncogenic contexts and that the fitness landscape shifts upon treatment. SIGNIFICANCE: By modeling complex genotypes in vivo, this study reveals key tumor suppressors that constrain the growth of EGFR-mutant tumors. Furthermore, we uncovered that KEAP1 inactivation reduces the sensitivity of these tumors to tyrosine kinase inhibitors. Thus, our approach identifies genotypes of biological and therapeutic importance in this disease.This article is highlighted in the In This Issue feature, p. 1601.
| S-EPMC8530463 | biostudies-literature
Project description:To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*. We used microarrys to directly compare geen expression of control and relapse tumors and identified gene sets specifically activated in relapse tumors. Control and relasped glioma samples upon mutant EGFR extinction were selected for RNA extraction and hybridization on Affymetrix microarrays.
2015-01-08 | E-GEOD-64751 | biostudies-arrayexpress
Project description:To determine the roles of oncogenic EGFR signaling in gliomagenesis and tumor maintenance, we generated a novel glioma mouse model driven by inducible expression of a mutant EGFR (EGFR*). Genetic suppression of EGFR* induction led to significant tumor regression and prolonged survival. But in spite of the initial response, the tumors relapsed invariably and propagated independent of EGFR*. We used microarrys to directly compare geen expression of control and relapse tumors and identified gene sets specifically activated in relapse tumors.
2015-01-08 | GSE64751 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286179 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286318 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286432 | GEO
Project description:EGFR amplification at extrachromosome DNAs (ecDNAs) is a major driving mutation in glioblastoma (GBM). However, targeting EGFR for GBM treatments remain unsatisfied. Here we identify a de novo long non-coding RNA (lncRNA) that is co-amplified with EGFR which we named hidden EGFR long non-coding downstream RNA (HELDR). HELDR is a GBM-specific lncRNA that promotes tumorigenicity independent of EGFR expression and signaling. HELDR globally binds genomic DNA and recruits a transcription co-activator p300 to the promoter of KAT7. p300-induced H3K27ac at KAT7 promoter enlists other co-transcription factors, activating KAT7 transcription. KAT7 induces H3K14ac H4K12ac that activate the transcription of KAT7-targeting gene programs critical for GBM malignancy. Targeting KAT7 synergistically enhances therapeutic effects of targeting EGFR for GBM treatment. These results not only reveal the role of HELDR in EGFR-driven GBM malignancy, but also provide strong rationale to characterize the roles of lncRNAs co-amplified with driver oncogenes at ecDNAs in human cancers.
2026-02-07 | GSE286319 | GEO