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S. Yano
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MINI 09 - Drug Resistance (ID 107)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:L. Villaruz, J. Minna
- Coordinates: 9/07/2015, 16:45 - 18:15, 205+207
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MINI09.12 - HDAC Inhibitors Overcome New Generation EGFR-TKI-Resistance Caused by Homozygous BIM Polymorphism in EGFR Mutant Lung Cancer (ID 885)
16:45 - 18:15 | Author(s): S. Yano
- Abstract
Background:
The BIM deletion polymorphism in intron 2 was found in a significant percent (~13%) of the Asian population, with 0.5% of individuals being homozygous for this deletion. Patients with EGFR mutant lung cancers harboring this BIM polymorphism have shorter progression free survival and overall response rates to 1[st] generation EGFR-TKIs, gefitinib and erlotinib. We recently reported that the histone deacetylase (HDAC) inhibitor vorinostat can epigenetically restore BIM function and death sensitivity of EGFR-TKI, in cases of EGFR mutant lung cancer where resistance to 1[st] generation EGFR-TKI is associated with a heterozygous BIM polymorphism. Here, we examined 1) whether BIM polymorphism associated with resistance to new generation EGFR-TKIs and 2) whether vorinostat could overcome EGFR-TKI resistance in EGFR mutant lung cancer cells with a homozygous BIM polymorphism.
Methods:
We used EGFR mutant lung cancer cells lines, PC-9, PC-9[i2BIM-/-] (a genetically engineered subclone that was homozygous for BIM deletion polymorphism), and PC-3 (heterozygous for BIM deletion polymorphism). These cell lines were treated with gefitinib, afatinib (2[nd] generation), and AZD9291 (3[rd] generation). Apoptosis was evaluated by FACS and expression of cleaved-caspase 3/7 and PARP by western blot.
Results:
While PC-9 cells were sensitive to all EGFR-TKIs in terms of apoptosis induction, both of PC-3 and PC-9[i2BIM-/- ] cells were resistant to 1[st] generation EGFR-TKIs and new generation EGFR-TKIs as well. Vorinostat combined with new generation EGFR-TKIs induced apoptosis of PC-3 and PC-9[i2BIM-/- ] cells in vitro. In the subcutaneous tumor model, AZD9291 regressed the tumors produced PC-9 cells but not PC-9[i2BIM-/- ] cells, indicating in vivo resistance of PC-9[i2BIM-/- ] cells to EGFR-TKIs. Combined use of vorinostat with AZD9291 successfully decreased the size of tumors produced by PC-9[i2BIM-/-] cells by inducing tumor cell apoptosis.
Conclusion:
These observations indicated that BIM deletion polymorphism is associated with apoptosis resistance caused not only by 1[st] generation EGFR-TKIs but also by new generation EGFR-TKIs. Moreover, combined use of HDAC inhibitor may overcome EGFR-TKI resistance associated not only with heterozygous deletion but also with homozygous deletion in the BIM gene.
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ORAL 42 - Drug Resistance (ID 160)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:R.C. Doebele, J.V. DeGregori
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 4a-4f
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ORAL42.07 - Discussant for ORAL42.04, ORAL42.05, ORAL42.06 (ID 3442)
18:30 - 20:00 | Author(s): S. Yano
- Abstract
- Presentation
Abstract not provided
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-004 - Aki1 as a Potential Therapeutics Target in CREB1 Signaling in Malignant Mesothelioma (ID 234)
09:30 - 17:00 | Author(s): S. Yano
- Abstract
Background:
Malignant pleural mesothelioma (MPM) is an aggressive tumor arising from the mesothelial cells of serosal membranes. Since current treatment options are largely ineffective, novel therapeutic strategies based on molecular mechanisms and the disease characteristics are needed to improve its prognosis. Akt kinase-interacting protein 1 (Aki1)/Freud-1/CC2D1A known as a scaffold protein of PI3K/PDK1/Akt that determines receptor signal selectivity for EGFR has been suggested as a therapeutic target in lung cancer. The aim of this study was to elucidate the role of Aki1 and its potential for treatment of MPM.
Methods:
We tested the effects of the treatment with Aki1 or CREB1 siRNAs on cell viability by MTT assay, cell cycle by FACS analysis, cell signaling by WB, and CREB transcriptional activity in 7 MPM cells and 1 mesothelial cells using in vitro experiments. We investigated the efficacy of Aki1 siRNA against growth of 211H cells in an orthotropic implantation model using SCID mice. We further examined Aki1 and p-CREB1 expressions in MPM tumors from 35 patients by TMA specimens and from 33 patients by the tissues.
Results:
Cell based assay showed that silencing of Aki1 inhibited cell viability and caused cell arrest of some of MPM cells but not mesothelial cells. Importantly, we identified that the efficacy of Aki1 is regulated by CREB1 signaling which is involved in cell viability, cell cycle, and transcriptional activity. Aki1 and phosphorylated CREB1 were frequently expressed in MPM patients (65/68 cases) (30/35 cases), respectively. Furthermore, the expression of Aki1 correlated with phosphorylation of CREB1 (Spearman rank correlations = 0.521; p = 0.002). Furthermore, direct application of Aki1 siRNA into the pleural cavity significantly inhibited growth of 211H cells compared with that of control siRNA in an orthotropic implantation model using SCID mice.
Conclusion:
Our data suggest an important role of Aki1/CREB axis in pathogenesis of MPM and provide a rationale for targeting Aki1 by intrathoracic therapy in locally advanced tumors.
