Dataset Information

EGFR-TKI-down-regulated proteins in HCC827 cells

ABSTRACT: EGFR mediates stabilities of a wide spectrum of proteins. Treatment of the cells with EGFR tyrosine kinase inhibitors (EGFR-TKIs) leads to degradation of these proteins. To define the proteins and corresponding pathways of EGFR-stabilized proteins, we use mass spectrum to quantify the protein levels in the untreated control HCC827 cells and the cells treated with erlotinib or gefitinib.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Li Zheng

LAB HEAD: Binghui Shen

PROVIDER: PXD050420 | Pride | 2025-05-13

REPOSITORIES: Pride

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Publications

EGFR-mediated HSP70 phosphorylation facilitates PCNA association with chromatin and DNA replication.

Wang Yingying Y Fernandez Anthony A Pei Xinyu X Liu Bing B Shen Lei L Yan Yao Y Solanki Hitendra S HS Yang Lin L Zhou Mian M Guo Yuming Y Wu Jun J Reckamp Karen L KL Zheng Li L Shen Binghui B

Nucleic acids research 20241101 21

Efficient DNA replication requires highly coordinated programs for the timely recruitment of protein complexes to DNA replication forks. Defects in this process result in replication stress, which in turn activates cell cycle checkpoints, suppresses cell proliferation and induces apoptosis. In response to persistent cell growth signals that speed up DNA replication processes, cells accelerate the recruitment of DNA replication proteins to avoid DNA replication stress. The mechanisms by which cel ...[more]

PMID: 39470734

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Project description:Despite initial and often dramatic responses of epidermal growth factor receptor (EGFR)-addicted lung tumors to the EGFR-specific tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, nearly all develop resistance and relapse. To explore novel mechanisms mediating acquired resistance, we employed non-small-cell lung cancer (NSCLC) cell lines bearing activating mutations in EGFR and rendered them resistant to EGFR-specific TKIs through chronic adaptation in tissue culture. In addition to previously observed resistance mechanisms including EGFR-T790M 'gate-keeper' mutations and MET amplification, a subset of the seven chronically adapted NSCLC cell lines including HCC4006, HCC2279 and H1650 cells exhibited marked induction of fibroblast growth factor (FGF) 2 and FGF receptor 1 (FGFR1) mRNA and protein. Also, adaptation to EGFR-specific TKIs was accompanied by an epithelial to mesenchymal transition (EMT) as assessed by changes in CDH1, VIM, ZEB1 and ZEB2 expression and altered growth properties in Matrigel. In adapted cell lines exhibiting increased FGF2 and FGFR1 expression, measures of growth and signaling, but not EMT, were blocked by FGFR-specific TKIs, an FGF-ligand trap and FGFR1 silencing with RNAi. In parental HCC4006 cells, cell growth was strongly inhibited by gefitinib, although drug-resistant clones progress within 10 days. Combined treatment with gefitinib and AZD4547, an FGFR-specific TKI, prevented the outgrowth of drug-resistant clones. Thus, induction of FGF2 and FGFR1 following chronic adaptation to EGFR-specific TKIs provides a novel autocrine receptor tyrosine kinase-driven bypass pathway in a subset of lung cancer cell lines that are initially sensitive to EGFR-specific TKIs. The findings support FGFR-specific TKIs as potentially valuable additions to existing targeted therapeutic strategies with EGFR-specific TKIs to prevent or delay acquired resistance in EGFR-driven NSCLC. Examination of mRNA levels in DMSO and gefitinib-resistant cultures of HCC4006 and HCC827. Each group has two replicates.

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