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Genome-wide profiling identifies the genetic dependencies of cell death following EGFR inhibition [RNA-Seq]

ABSTRACT: EGFR is a proto-oncogene that is mutationally activated in a variety of cancers. Small molecule inhibitors targeting EGFR can effectively slow the progression of disease, and in some settings, these drugs even cause dramatic tumor regression. However, responses to EGFR inhibitors are rarely durable, and the mechanisms contributing to response variation remain unclear. In particular, several distinct mechanisms have been proposed to explain how EGFR inhibition activates cell death, and a consensus has yet to emerge. In this study, we use functional genomics with specialized analyses to infer how genetic perturbations affect the drug-induced death rate. Our data clarify that inhibition of PI3K signaling drives the lethality of EGFR inhibition. Inhibition of other pathways downstream of EGFR, including the RAS-MAPK pathway, promotes growth suppression but not the lethal effects of EGFR inhibitors. Taken together, our study provides a “reference map” for the genome-wide genetic dependencies of lethality in response to EGFR inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE323366 | GEO | 2026/03/10

REPOSITORIES: GEO

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Genome-wide profiling identifies the genetic dependencies of cell death following EGFR inhibition

Project description:EGFR is a proto-oncogene that is mutationally activated in a variety of cancers. Small molecule inhibitors targeting EGFR can effectively slow the progression of disease, and in some settings, these drugs even cause dramatic tumor regression. However, responses to EGFR inhibitors are rarely durable, and the mechanisms contributing to response variation remain unclear. In particular, several distinct mechanisms have been proposed to explain how EGFR inhibition activates cell death, and a consensus has yet to emerge. In this study, we use functional genomics with specialized analyses to infer how genetic perturbations affect the drug-induced death rate. Our data clarify that inhibition of PI3K signaling drives the lethality of EGFR inhibition. Inhibition of other pathways downstream of EGFR, including the RAS-MAPK pathway, promotes growth suppression but not the lethal effects of EGFR inhibitors. Taken together, our study provides a “reference map” for the genome-wide genetic dependencies of lethality in response to EGFR inhibitors.

2026-03-10 | GSE323365 | GEO

TRANSCRIPTIONAL EFFECTS OF INHIBITING EGFR IN KERATINOCYTES

Project description:EGFR activation is important in human epithelial malignancies, including cutaneous squamous cell carcinoma, lung, colon, pancreatic and other cancers. Therapies targeting EGFR are currently used to treat such cancers, but one significant drawback to EGFR inhibitor therapies is the associated skin toxicity. This toxicity usually presents as papular or pustular folliculitis, dry skin with pruritus and hair and nails abnormalities. The side effects often limit the usefulness of EGFR inhibitors in cancer treatment. The transcriptional changes caused by EGFR inhibition in epidermal keratinocytes have not been extensively explored. To define the transcriptional changes caused by inhibition of EGFR in primary human epidermal keratinocytes, we treated these cells with Tyrphostin and compared treated and control cultures in parallel, using Affymetrix microarrays. Using metaanalysis approaches, we integrated the observed changes with a large set of already existing data on transcriptional profiling in epidermal keratinocytes. We found that EGFR inhibition suppresses expression of genes associated with keratinocyte proliferation, attachment and motility. Apoptosis is facilitated by both induction of proapoptotic and suppression of antiapoptotic genes. Surprisingly, EGFR inhibition induces expression of markers of epidermal differentiation. Time course of human epidermal keratinocytes treated with Tyrphostin (AG1478) and untreated controls

2012-10-19 | E-GEOD-41680 | biostudies-arrayexpress

Genome-wide CRISPR screening reveals genetic modifiers of mutant EGFR dependence in NSCLC

Project description:Human non-small-cell lung cancers (NSCLCs) harboring activating mutations in epidermal growth factor receptor (EGFR) frequently respond to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib and gefitinib. However, the responses are not durable, and the magnitude of tumor regression is variable, suggesting the existence of genetic modifiers of EGFR dependency in EGFR-mutant NSCLCs. Here, we applied a genome-wide CRISPR-Cas9 screening to identify genetic determinants of EGFR TKI sensitivity and uncovered both known and putative candidates. Specifically, we show that knockout of RIC8A, a guanine nucleotide exchange factor (GEF) essential for G-alpha protein activation, enhanced EGFR TKI-induced cell death and prevented acquired resistance. Mechanistically, we demonstrate that RIC8A is a potent positive regulator of the pro-survival YAP signaling pathway, activation of which rescued the EGFR TKI sensitizing phenotype resulting from RIC8A knockout. We also show that knockout of ARIH2, or other components in the Cullin-5 E3 ubiquitin ligase complex, conferred resistance to EGFR inhibition, in part by promoting nascent protein synthesis through METAP2. Together, these data uncover a spectrum of previously unidentified regulators of EGFR TKI sensitivity in EGFR-mutant NSCLC cells, providing insights into the heterogeneity of EGFR TKI treatment responses in EGFR-mutant NSCLCs.

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The role of S100A9 in brain metastesis in EGFR-mutant lung cancer

Project description:Metastatic relapse from treatment failure has been a formidable challenge to finding a cure for EGFR-mutant lung cancer. Metastasis to the brain is a severe complication for 45% of patients with EGFR-mutant lung cancer that drastically reduces their quality of life and survival. Here, we demonstrate that genetic inhibition of S100A9, ALDH1A1, RAR, or pharmacological inhibition of the RA pathway using pan-RAR inhibitors significantly reduces brain relapse from osimertinib-refractory cancer cells. Our study has therefore revealed a novel S100A9-ALDH1A1-RA signaling axis in the EGFR-mutant lung cancer cells that drives osimertinib-refractory metastatic brain relapse and identified a potential vulnerability in lung cancer cells that can be therapeutically targeted to prolong progression-free survival in EGFR-mutant lung cancer patients.

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Aberrant ERK signaling causes resistance to EGFR kinase inhibitors

Project description:The clinical efficacy of EGFR kinase inhibitors is limited by the development of drug resistance. The irreversible EGFR kinase inhibitor WZ4002 is effective against the most common mechanism of drug resistance mediated by the EGFR T790M mutation. Here we show that in multiple complementary models harboring EGFR T790M, resistance to WZ4002 develops through aberrant activation of ERK signaling caused by either an amplification of MAPK1 or by downregulation of negative regulators of ERK signaling. Inhibition of MEK or ERK restores sensitivity to WZ4002, and the combination of WZ4002 and a MEK inhibitor prevents the emergence of drug resistance. The WZ4002 resistant MAPK1 amplified cells also demonstrate an increase both in EGFR internalization and a decrease in sensitivity to cytotoxic chemotherapy compared to the parental counterparts. Our findings provide insights into mechanisms of drug resistance to EGFR kinase inhibitors and highlight rational combination therapies that should be evaluated in clinical trials. Our study identifies ERK signaling as a mediator of resistance to irreversible pyrimidine EGFR inhibitors in EGFR T790M-bearing cancers. We further provide a therapeutic strategy to both treat and prevent the emergence of this resistance mechanism. To generate drug-resistant NCI-H1975 cell lines, non-small cell lung cancer (NSCLC) cells were exposed to increasing concentrations of WZ4002 similar to previously described methods. Individual clones from WZ4002-resistant (WZR) cells were isolated and confirmed to be drug resistant. Clone #6, designated as WZR6, was used in this study. For expression analysis, samples were prepared in triplicate from parental NCI-H1975 and NCI-H1975 WZR6 cells.

2012-10-01 | E-GEOD-37699 | biostudies-arrayexpress

Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC

Project description:EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.

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Targeted inhibition of human breast cancer cell lines selected as model systems of ERBB2-positive/EGFR high breast cancer [RPPA-SKBR3]

Project description:EGFR-inhibition is required for targeted therapies of ERBB2-positive/EGFR high breast cancer. Approximately 30% of human ERBB2-positive breast tumors also express EGFR. Three targeted therapeutics (erlotinib, pertuzumab, trastuzumab) and two ligands (EGF, HRG) were analyzed in all possible combinations. Each experiment involving inhibition with targeted drugs was performed in three, and measurements without inhibitors were performed in five biological replicates. This resulted in 780 samples. Incubation with therapeutics only and dilution series of control lysated were included as controls.

2012-10-22 | E-GEOD-36326 | biostudies-arrayexpress

Targeted inhibition of human breast cancer cell lines selected as model systems of ERBB2-positive/EGFR high breast cancer [RPPA-HCC1954]

2012-10-22 | E-GEOD-36324 | biostudies-arrayexpress

TRANSCRIPTIONAL EFFECTS OF INHIBITING EGFR IN KERATINOCYTES

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Identification of stable markers of EGFR inhibitor resistance in breast cancer

Project description:EGFR expression in primary mammary tumors predicts for decrease patient surival, but targeted EGFR inhibitors have failed to improve patient outcomes. To identifiy mediators of resistance to EGFR inhibition in breast cancer, normal murine mammary gland (NMuMG) cells specifcally transformed by overexpression of EGFR (NME) were cultured under 3D conditions in the presence of the EGFR inhibitor AG1478. Using this approach we were able to isolate a cell conlony that demonstrated sponaneous resistance to inhibition of EGFR. These AG1478 resistant (AGR) cells were expanded in vitro and analysed by microarray.

2020-12-01 | GSE140978 | GEO

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