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The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE193259 | GEO | 2022/04/06

REPOSITORIES: GEO

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The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells.

Project description:Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.

| S-EPMC9794691 | biostudies-literature

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ChIP-seq]

2022-04-06 | GSE193257 | GEO

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ATAC-seq]

2022-04-06 | GSE193256 | GEO

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [RNA-seq]

2022-04-06 | GSE193258 | GEO

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells

Project description:The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells

| PRJNA795497 | ENA

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ATAC-seq]

Project description:The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ATAC-seq]

| PRJNA795501 | ENA

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [RNA-seq]

Project description:The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [RNA-seq]

| PRJNA795502 | ENA

The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ChIP-seq]

Project description:The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells [ChIP-seq]

| PRJNA795500 | ENA

Drug tolerant persister cells of EGFR-mutant cell line under kinase-inhibitor combination

Project description:Drug tolerant persister cells of EGFR-mutant PC9 cell lines surviving treatment with kinase inhibitor combination. Cells were treated with combination of erlotinib, osimertinib, trametinib and dasatinib and surviving cells were harvested for RNA extraction. 3' UTR RNA-seq profiles were compared to parental control cells and to outgrowing cells after treatment had been removed

2023-06-30 | E-MTAB-13045 | biostudies-arrayexpress

The Ontogeny and Vulnerabilities of Lapatinib Drug Tolerant Persisters [Parental (P) vs. Drug-Tolerant Persister (DTP)]

Project description:Despite significant advances in HER2-targeted therapies, therapeutic resistance in HER2-positive (HER2+) breast cancer remains a significant clinical problem, especially in the metastatic setting. “Drug tolerant persisters” (DTPs), a sub-population of cancer cells that survive via reversible, non-genetic mechanisms, are implicated in resistance to tyrosine kinase inhibitors (TKIs) in several cancer models, but DTPs for HER2-targeted TKIs (e.g., lapatinib, neratinib, tucatinib) have not been characterized extensively. Here, we report that HER2+ER+ and HER2+ER- breast cancer lines give rise to distinct types of “lapatinib-DTPs,” characterized by different transcriptional programs and sensitivity to lapatinib/anti-estradiol combination. Lapatinib-DTPs from HER2+/ER+ cells rewire the PI3K/AKT/mTORC1 pathway via transcriptional induction of SGK3 to enable AKT-independent mTORC1 activation and survival. Lentiviral barcoding experiments, combined with single cell RNA-sequencing, suggest that HER2+ cells stochastically cycle through a cell state (“pre-DTP”) capable of transition to DTPs. Collectively, our results provide insight into DTP ontogeny and therapeutic vulnerabilities.

2021-12-31 | GSE155341 | GEO

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