EGFR-Mutant SCLC Exhibits Heterogeneous Phenotypes and Resistance to Common Antineoplastic Drugs
Journal
Journal of Thoracic Oncology
Journal Volume
14
Journal Issue
3
Pages
513-526
Date Issued
2019
Author(s)
Lin C.-A.
Chen H.-Y.
Lin S.-U.
Chang C.-C.
Abstract
Introduction: Approximately 5% of patients with EGFR-activating mutations acquire EGFR tyrosine kinase inhibitor (TKI) resistance through SCLC transformation. However, the reason for the poor outcome and the molecular basis of EGFR-mutant SCLC that has transformed from adenocarcinoma remain unclear. Methods: In this study, we established two EGFR-mutant SCLC cell lines from lung adenocarcinoma patients after failed EGFR-TKI treatment to investigate their molecular basis and potential therapeutic strategies in the hope of improving patient outcome. Results: These two EGFR-mutant SCLC cell lines displayed two different phenotypes: suspensive and adherent. Both phenotypes shared the same genomic alterations analyzed by array-based comparative genomic hybridization assay. Increased expression of EGFR and mesenchymal markers and decreased expression of neuroendocrine markers were observed in adherent cells. Principal component analysis and hierarchical clustering analysis of RNA microarray revealed that these two cell lines displayed a unique gene expression pattern that was distinctly different from that in NSCLC and classical SCLC cells. Combined treatment using an EGFR-TKI and an AKT inhibitor attenuated cell viabilities in our two cell lines. Moreover, the use of a histone deacetylase inhibitor significantly inhibited the cell viabilities of both cell lines in vitro and in vivo. Conclusion: Our findings suggest that EGFR-mutant SCLC may be a distinct subclass of SCLC that exhibits epithelial-mesenchymal transition phenotypes, and adding an AKT or histone deacetylase inhibitor to pre-existing therapies may be one of the therapeutic choices for transformed EGFR-mutant SCLC. ? 2018 International Association for the Study of Lung Cancer
SDGs
Other Subjects
alpha tubulin; epidermal growth factor receptor; Hermes antigen; histone deacetylase 1; histone deacetylase 2; mitogen activated protein kinase; neurogenic differentiation factor; protein kinase B; protein p53; protein tyrosine kinase inhibitor; romidepsin; synaptophysin; vimentin; antineoplastic agent; EGFR protein, human; epidermal growth factor receptor; amino acid sequence; animal experiment; animal model; antigen expression; antineoplastic activity; Article; cell count; cell invasion; cell proliferation; cell viability; comparative genomic hybridization; controlled study; drug efficacy; EGFR gene; enzyme activation; enzyme phosphorylation; gene; gene expression; gene mutation; human; human cell; IC50; in vitro study; in vivo study; lung adenocarcinoma; lung cancer cell line; lung carcinogenesis; lung non-small cell carcinoma cell line; microarray analysis; missense mutation; mouse; nonhuman; nonsense mutation; priority journal; protein depletion; protein expression; RB1 gene; small cell lung cancer; small cell lung cancer cell line; TP53 gene; transcription regulation; treatment duration; treatment outcome; tumor volume; whole genome sequencing; animal; apoptosis; drug resistance; drug screening; epithelial mesenchymal transition; female; genetics; lung adenocarcinoma; lung tumor; middle aged; mutation; nonobese diabetic mouse; pathology; phenotype; SCID mouse; small cell lung cancer; tumor cell culture; Adenocarcinoma of Lung; Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Drug Resistance, Neoplasm; Epithelial-Mesenchymal Transition; ErbB Receptors; Female; Humans; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Middle Aged; Mutation; Phenotype; Small Cell Lung Carcinoma; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
Type
journal article