title: Histone Deacetylase 3 Inhibition OvercomesBIMDeletion Polymorphism-Mediated Osimertinib Resistance inEGFR-Mutant Lung Cancer.
abstract: Purpose:TheBIMdeletion polymorphism is associated with apoptosis resistance to EGFR tyrosine kinase inhibitors (EGFR-TKI), such as gefitinib and erlotinib, in non-small cell lung cancer (NSCLC) harboringEGFRmutations. Here, we investigated whether theBIMdeletion polymorphism contributes to resistance against osimertinib, a third-generation EGFR-TKI. In addition, we determined the efficacy of a histone deacetylase (HDAC) inhibitor, vorinostat, against this form of resistance and elucidated the underlying mechanism.Experimental Design:We usedEGFR-mutated NSCLC cell lines, which were either heterozygous or homozygous for theBIMdeletion polymorphism, to evaluate the effect of osimertinibin vitroandin vivoProtein expression was examined by Western blotting. Alternative splicing ofBIMmRNA was analyzed by RT-PCR.Results:EGFR-mutated NSCLC cell lines with theBIMdeletion polymorphism exhibited apoptosis resistance to osimertinib in a polymorphism dosage-dependent manner, and this resistance was overcome by combined use with vorinostat. Experiments with homozygousBIMdeletion-positive cells revealed that vorinostat affected the alternative splicing ofBIMmRNA in the deletion allele, increased the expression of active BIM protein, and thereby induced apoptosis in osimertinib-treated cells. These effects were mediated predominantly by HDAC3 inhibition. In xenograft models, combined use of vorinostat with osimertinib could regress tumors inEGFR-mutated NSCLC cells homozygous for theBIMdeletion polymorphism. Moreover, this combination could induce apoptosis even when tumor cells acquiredEGFR-T790M mutations.Conclusions:These findings indicate the importance of developing HDAC3-selective inhibitors, and their combined use with osimertinib, for treatingEGFR-mutated lung cancers carrying theBIMdeletion polymorphism.Clin Cancer Res; 23(12); 3139-49. ©2016 AACR.
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Tanimoto
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Takeuchi
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Arai
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: Tadaaki
authors.initials: T
authors.lastname: Yamada
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Xavier
authors.initials: X
authors.lastname: Roca
authors.affiliation: Cancer & Stem Cell Biology Signature Research Programme, Duke-NUS Medical School, Singapore.|Department of Medical Oncology, National Cancer Centre Singapore, Singapore.|Department of Haematology, Singapore General Hospital, Singapore.|Department of Medicine, Duke University Medical Center, Durham, North Carolina.
authors.forename: S Tiong
authors.initials: ST
authors.lastname: Ong
authors.affiliation: Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. syano@staff.kanazawa-u.ac.jp.
authors.forename: Seiji
authors.initials: S
authors.lastname: Yano
mesh_terms: D000178:Acrylamides; D000814:Aniline Compounds; D017209:Apoptosis / Q000187:drug effects; D000072224:Bcl-2-Like Protein 11 / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006655:Histone Deacetylases / Q000008:administration & dosage / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000009:adverse effects; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D017384:Sequence Deletion; D000077337:Vorinostat; D000099186:Histone Deacetylase 3; D007211:Indoles; D011743:Pyrimidines
chemical_list: D000178:Acrylamides; D000814:Aniline Compounds; D000072224:Bcl-2-Like Protein 11; D066246:ErbB Receptors; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D000077337:Vorinostat; D000099186:Histone Deacetylase 3; C000596361:osimertinib; D007211:Indoles; D011743:Pyrimidines; C512478:EGFR protein, human