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Acquired resistance to mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling

ABSTRACT: To compare gene copy number in cell populations with acquired resistance to specified EGFR inhibitors to parental cell lines. The aim of the experiment was to determine whether gain or loss of copy number of particular genes was associated with resistance to particular EGFR inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE59239 | GEO | 2015/04/14

SECONDARY ACCESSION(S): PRJNA254803

REPOSITORIES: GEO

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Acquired resistance to mutant-selective EGFR inhibitor AZD9291 is associated with increased dependence on RAS signaling

Project description:To compare gene copy number in cell populations with acquired resistance to specified EGFR inhibitors to parental cell lines. The aim of the experiment was to determine whether gain or loss of copy number of particular genes was associated with resistance to particular EGFR inhibitors. Comparing gene copy number in PC9 parental cells to gene copy number in 5 cell populations resistant to AZD9291, 2 cell populations resistant to WZ4002, 2 cell populations resistant to afatinib and 4 cell populations resistant to gefitinib.

2015-04-14 | E-GEOD-59239 | biostudies-arrayexpress

Microarray study to understand acquired resistance to EGFR-targeted therapy in lung cancer

Project description:Activating mutations of EGFR have been characterized as important mechanisms for carcinogenesis in a subset of EGFR-dependent non-small cell lung cancers (NSCLC). EGFR tyrosine kinase inhibitors (TKI), such as erlotinib and gefitinib, have dramatic clinical effects on EGFR-addicted lung cancers and are used as first-line therapy for EGFR-mutant tumors. However, eventually all tumors acquire secondary resistance to the drugs and progress. We established a model to better understand mechanisms of acquired resistance. NCI- HCC827 cells are EGFR-mutant and highly erlotinib-sensitive. In this study we exposed HCC827 cells to increasing concentrations of erlotinib and two highly erlotinib-resistant subclones were developed (ER3 and T15-2). In these subclones no acquired alterations of EGFR or MET were found. We hereby performed a gene expression microarray studies to understand changes that might explain mechanisms of resistance. Through these studies we demonstrated in one resistant clone (ER3) overexpression of AXL, a tyrosine kinase implicated in imatinib and lapatinib resistance. Gene expression profilings were measured in NSCLC cell line HCC827 and two erlotinib-resistant HCC827-originated sublines ER3 and T15-2.

2012-05-29 | E-GEOD-38310 | biostudies-arrayexpress

Microarray study to understand acquired resistance to EGFR-targeted therapy in lung cancer

2012-05-30 | GSE38310 | GEO

Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: Cuto28

Project description:ALK and ROS1 fusions defines subsets of lung adenocarcinoma. Although ALK/ROS1 inhibitors improved therapeutic outcome of patients harboring those oncogenic fusions, complete responses were rare, and resistance eventually develops from the residual tumor. To under the mechanisms contributing to residual tumor formation, we performed phosphoproteomics to explore the signaling adaption shortly after ALK/ROS1 inhibition. We found the phosphorylation of Mig6, a potent inhibitor for EGFR, was decreased following ALK/ROS1 inhibition, impairing Mig6 binding and inhibition on EGFR. Furthermore, Mig6 mRNA and protein levels were decreased rapidly by ALK/ROS1 inhibitors, potentiating EGFR activity to support cell survival. We also uncovered a novel mechanism mediated by Mig6 to regulate EGFR activity without impacting EGFR phosphorylation, but rather altering signaling adaptor SHC1 binding to EGFR. Mig6 expression was also lost following long-term exposure to ALK/ROS1 inhibitors to support EGFR-mediated acquired resistance. Finally, a Mig6 EGFR-binding domain truncation mutation was identified in a patient-derived ROS1 cell line, rendering its resistance to ROS1 inhibitors but sensitivity to HER family inhibitors. Our work established a rationale to evaluate combinations of ALK/ROS1 and EGFR inhibitors to limit residual tumor formation, therefore preventing or delaying subsequent resistance emergence.

2023-09-12 | PXD036771 | Pride

Mig6 mediates adaptive and acquired resistance to ALK and ROS1 fusion kinase inhibition through feedback activation of EGFR: H3122

2023-09-12 | PXD036772 | Pride

Vitamin D3 Metabolites Demonstrate Prognostic Value in EGFR-Mutant Lung Adenocarcinoma and Can be Deployed to Oppose Acquired Therapeutic Resistance

Project description:EGFR tyrosine kinase inhibitors (EGFR TKIs) are the standard of care treatment for patients with EGFR-mutant lung adenocarcinoma (LUAD). Although initially effective, EGFR TKIs are not curative. Disease inevitably relapses due to acquired drug resistance. Here, we tested the ability of 1,25(OH)2D3 to promote epithelial differentiation and restore EGFR TKI sensitivity in models of EGFR TKI resistance that were associated with epithelial–mesenchymal transition (EMT).

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Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors

Project description:This SuperSeries is composed of the following subset Series: GSE37698: Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors (SNP array) GSE37699: Aberrant ERK signaling causes resistance to EGFR kinase inhibitors Refer to individual Series

2012-10-01 | E-GEOD-37700 | biostudies-arrayexpress

Reactivation of ERK signaling causes resistance to EGFR kinase inhibitors (SNP array)

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. The EGFR mutant non-small cell lung cancer (NSCLC) cell line PC9 GR4 (delE746_A750/T790M) was 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. Number of samples: 5. PC9GR4 as a control. 4 clones of WZ4002-resistant PC9GR4.

2012-10-01 | E-GEOD-37698 | biostudies-arrayexpress

3' UTR RNA-sequencing of human EGFR-mutant PC9 cells that were CRISPR engineered to additionally contain EGFR-mutations T790M and C797S

Project description:Lung adenocarcinoma PC9 cells were engineered to not only contain the driving EGFR-mutations, but also EGFR T790M and EGFR C797S that provide resistance to EGFR inhibitors.

2021-07-19 | E-MTAB-9887 | 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.

2019-11-14 | PXD014198 | Pride

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