title: Potential effect of spliceosome inhibition in small cell lung cancer irrespective of the MYC status.
abstract: Small cell lung cancer (SCLC) is a highly aggressive malignancy with few therapeutic advances in the treatment in recent decades. Based on a recent study that identified the spliceosome as a therapeutic vulnerability in MYC-driven breast cancers, we evaluated the efficacy of a spliceosome inhibitor in SCLC cell lines and analyzed the correlation with MYC status. Among 23 SCLC cell lines examined, eight showed high MYC protein expression (> 80% positive cells) by immunohistochemistry (IHC), while 10 cell lines demonstrated no staining for MYC. The remaining five cell lines showed weak staining (< 40% positive cells). All four cell lines that were previously demonstrated to have MYC gene amplification were positive for MYC by IHC. Four cell lines with high MYC expression and four with low MYC expression were used in further analysis. A spliceosome inhibitor, pladienolide B, showed high efficacy (IC50 < 12nM) in all eight cell lines tested, irrespective of the MYC IHC or MYC gene amplification status. We observed that the four cell lines with higher sensitivity to the spliceosome inhibitor were established from patients with prior chemotherapy. Therefore we chronically treated H1048 cells, that were established from a treatment-naïve patient, with cisplatin for 4 weeks, and found that H1048-cisplatin treated cells became more sensitive to pladienolide B. In conclusion, our in vitro results indicate that spliceosome inhibitors would be promising molecular target drugs in SCLC irrespective of the MYC status, especially in the second-line settings after an effective front-line chemotherapy.
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.|Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Kenichi
authors.identifier: http://orcid.org/0000-0002-0842-8832
authors.initials: K
authors.lastname: Suda
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Leslie
authors.initials: L
authors.lastname: Rozeboom
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Hui
authors.initials: H
authors.lastname: Yu
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Kim
authors.initials: K
authors.lastname: Ellison
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Rivard
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
authors.affiliation: Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D055752:Small Cell Lung Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017381:Spliceosomes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004852:Epoxy Compounds; D018942:Macrolides; D016271:Proto-Oncogene Proteins c-myc; C522342:pladienolide B; D002945:Cisplatin