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T. Yamada
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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 - 09:30 | Author(s): T. Yamada
- 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.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-018 - Whole Transcriptome Analysis of EGFR Wildtype Non-Small Cell Lung Cancer Patients with Clinical Benefit from Erlotinib (ID 2357)
09:30 - 09:30 | Author(s): T. Yamada
- Abstract
Background:
Despite the success of targeted assays of EGFR mutations in defining the non-small cell lung cancer patients who benefit from EGFR-tyrosine kinase inhibition, there still remains a significant portion of patients whose tumors do not harbor EGFR mutations, yet achieve clinical benefit (progression-free survival > 6 months) from erlotinib treatment. We apply whole transcriptome sequencing (RNAseq) to discover expression and mutation changes associated with erlotinib response.
Methods:
We report the results of 108 stage IV non-small cell lung cancer patients treated with first line erlotinib. The primary endpoint assessed was progression-free survival (PFS), to which erlotinib has already shown to be beneficial when compared to placebo. Furthermore, RNAseq was performed on 73 tumors from 29 (40%) males and 44 (60%) females. The RNAseq samples were processed to obtain mutation and expression data.
Results:
108 patients were followed for PFS, 7 of which declined to be followed, 2 came off erlotinib due to toxicity, 3 died before completion of the first cycle of erlotinib, 5 were ineligible, and 2 have not had tumor recurrence to date. The remaining 92 patients had a mean PFS of 4.71 months (±1.03 months, 95% CI). No patients experienced a complete response, and 14 of 92 (15%) patients had a partial response. Of the tumors analyzed via RNAseq, 7 harbored EGFR mutations, including a complex exon 18 deletion in a patient with a partial response to erlotinib. 14 of 64 (22%) patients without EGFR mutations showed clinical benefit from erlotinib, none of which harbored other known actionable mutations. These EGFR wildtype tumors did not exhibit mutations in other known oncogenes in lung cancer. We hypothesize that they are addicted to EGFR signaling through other means than overactive kinase activity caused by activating mutations. Figure 1
Conclusion:
We present results from a clinical trial of first line erlotinib in stage IV non-small cell lung cancer. We show that there is a significant cohort of EGFR wildtype patients who receive clinical benefit from erlotinib and present preliminary data of their mutation status.
