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Dissecting EGFR Inhibitor Resistance in Glioblastoma through genome-wide CRISPR screening

Dissecting EGFR Inhibitor Resistance in Glioblastoma through genome-wide CRISPR screening
通过全基因组 CRISPR 筛选剖析胶质母细胞瘤中的 EGFR 抑制剂耐药性
批准号:
9760731
负责人:
Colin Patrick Tang
金额:
$4.5万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-03-01 至 2022-02-28
关键词:
AcuteAdultAmino Acid TransporterAmino AcidsAntibodiesApoptosisAutophagocytosisBiochemicalBiochemical GeneticsBiologicalBrainBypassCRISPR screenCell LineCell ProliferationCellsClinicalClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyDataDiseaseDrug resistanceEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorErlotinibExtracellular DomainFRAP1 geneGene AmplificationGenerationsGenesGenetic TranscriptionGenotypeGlioblastomaGliomaGoalsGrowth Factor ReceptorsHemeHumanIn VitroLibrariesMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of lungMapsMeasuresMediatingMediator of activation proteinMemorial Sloan-Kettering Cancer CenterMetabolic PathwayModelingMolecularMutationNon-Small-Cell Lung CarcinomaOncogenicPTEN genePathogenesisPathway interactionsPatientsPenetrancePharmaceutical PreparationsPhosphorylationPhosphotransferasesPlayProliferatingProtein IsoformsProto-Oncogene Proteins c-aktReceptor ActivationReceptor InhibitionRegulationResearchResistanceRoleSeriesSignal PathwaySignal TransductionStarvationTSC1 geneTSC2 geneTestingTherapeutic EffectTranslatingTreatment EfficacyTumor Suppressor ProteinsTumor-DerivedValidationVirus Diseasesactivating transcription factoramino acid metabolismbasebiological adaptation to stressdeprivationdesignendoplasmic reticulum stressexperimental studyfollow-upgain of function mutationgenome-widein vitro Modelin vivoinhibitor/antagonistkinase inhibitorlapatinibmembermutantnovelnovel therapeutic interventionreceptorresponsesensorstressortumor

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英文摘要
PROJECT SUMMARY/ABSTRACT Drug resistance represents a major problem in glioblastoma (GBM), the most common and aggressive malignant brain tumor in adults. GBM cells that proliferate and survive through aberrant activation of kinase signaling pathways are believed to avoid the deleterious effects of therapeutic kinase inhibition through utilization of alternative signaling and metabolic pathways. The epidermal growth factor receptor (EGFR) represents a compelling example to dissect this question because at least 40% of human GBMs harbor an EGFR alteration, and inhibitors of this pathway (EGFRi) have been largely ineffective thus far. Despite considerable progress in understanding EGFRi resistance in other cancers (most notably, non-small cell lung cancer), mechanisms of EGFRi resistance in GBM remain poorly understood. To identify novel mechanisms of EGFR kinase inhibitor resistance in GBM, I have performed genome-scale clustered regularly interspaced short palindromic repeats (CRISPR) library screens in several EGFR-mutant GBM cell lines in the presence and absence of the pan-ErbB inhibitor neratinib. Loss of multiple members of the amino-acid sensing pathway (e.g., GCN2, GCN1L1) were associated with neratinib resistance in these cell lines. I have also observed that acute EGFR inhibition induces the amino acid sensing pathway (e.g., phosphorylation of EIF2a and ATF4 expression). Based on these results, I hypothesize that EGFR inhibition induces a state of amino acid starvation and activation of the integrated stress response (ISR) which can be bypassed by loss of GCN2 or other related genes in the ISR pathway. I propose to elucidate this novel mechanism of EGFR inhibitor resistance through a series of biochemical and genetic experiments and further explore its broader biological significance in genetically characterized, patient-derived human GBM models. My overall goal is to further understand the molecular and cellular consequences of EGFR inhibition, with the goal of designing more effective therapeutic strategies for patients with EGFR-altered GBM.
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