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Takashi Kohno
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ES 04 - Biology of Lung Cancer (ID 513)
- Event: WCLC 2017
- Type: Educational Session
- Track: Biology/Pathology
- Presentations: 1
- Moderators:Vera Luiza Capelozzi, Akihiko Gemma
- Coordinates: 10/17/2017, 11:00 - 12:30, F201 + F202 (Annex Hall)
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ES 04.01 - Novel Targetable Oncogenes in Lung Cancer (ID 7597)
11:00 - 12:30 | Presenting Author(s): Takashi Kohno
- Abstract
- Presentation
Abstract:
Aberrations of oncogenes, such as EGFR mutation; and ALK and ROS1 fusions, function as a driver in the development of lung adenocarcinoma (LADC) and are established therapeutic targets. We previously identified RET fusion present in 1-2% of LADC (Kohno, Ichikawa, Nat Med, 2012). Its activity as an oncogenic driver in lung carcinogenesis was validated by a study of transgenic mice expressing KIF5B-RET cDNA in their lungs (Saito, Carcinogenesis, 2014). RET fusion is likely to be another target of therapy using tyrosine kinase inhibitors, as represented by a high response rate of RET-fusion positive LADC to vandetanib (LURET study, Yoh et al., Lancet Resp Med, 2016). Our genome-wide sequencing study revealed that ALK, RET and ROS1 oncogene fusion-positive LADCs carry less numbers of mutations in cancer-related genes than others (Saito, Cancer Res, 2015), indicating a small mutation burden in the development of the formers. On the other hand, >30% of LADC and most of other types of lung cancers are negative for the oncogene aberrations above, therefore, other therapeutic targets are needed for precision lung cancer medicine. We have revealed frequent inactivation of chromatin-regulating genes, such as SMARCA4/BRG1 and CREBBP, in lung cancers negative for oncogene aberrations (Ogiwara et al, Cancer Discovery, 2016). We propose a synthetic lethal therapeutic method for chromatin regulator-deficient lung cancers based on inhibition of paralog proteins. LADC driven by somatic EGFR mutations is more prevalent in East Asians (30-50%) than in European/Americans (10-20%). We recently revealed that variations in HLA-class II loci underlie the risk of the disease, by conducting a genome-wide association study of 3,173 EGFR-LADC patients and 15,158 controls (Shiraishi et al., Nature Comm, 2016). The result indicates that LADC develops in vivo through interaction between somatic oncogene mutations and germline variations that modulate immune reaction. We would like to discuss here precision lung cancer medicine based on information on cancer and the host genomes.
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P3.02 - Biology/Pathology (ID 620)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Biology/Pathology
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.02-035 - Mutational Signatures and Their Association with Clinicopathological Features in Lung Adenocarcinoma of Smokers (ID 8623)
09:30 - 16:00 | Author(s): Takashi Kohno
- Abstract
Background:
Lung adenocarcinoma (LADC) harboring druggable driver oncogene such as EGFR mutation and ALK fusion can be treated with molecular-targeted drugs. These oncogene aberrations are frequently observed in LADCs of never-smoker, while LADCs of smokers often lack such druggable oncogene aberrations. Therefore, understanding mutation profile of LADCs of smokers is required to improve precision lung cancer medicine..
Method:
We analyzed mutational signatures of somatic mutations in 373 LADCs (smoker 220 cases; 59%, never-smoker 153 cases; 31%) of Japanese using whole exome sequencing data. Four mutational signatures were identified by non-negative matrix factorization and logistic regression analysis. We are now analyzing significantly mutated gene (SMG)s by MutSigCV1.5 of LADCs of smokers and associations of each signature with clinicopathological factors including histological subtype and prognosis.
Result:
Indel mutations as well as well-characterized C>A mutations were defined as mutational event more prevalent in LADC of ever-smokers than in never-smokers (P=8.76E-15 and P=0.000417 respectively). A novel set of genes were identified as a main target for indel mutations (7.4%; 22 of 296 samples), and their mutations were significantly associated with smoking and with UIP co-occurrence in their lung (P=0.0068 and P=0.037, respectively). Indel mutations in 3’-UTRs of these genes caused specific reduction in mutant transcripts, while those in coding region caused truncation of polypeptide.
Conclusion:
A novel gene set including those in 3’-UTR, would contribute to LADC development in smokers and associated with usual interstitial pneumonia, by promoting undifferentiation of tumor cells.
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P3.02-041 - EGFR Amplification Mediates Resistance to TAS121, A Third-Generation EGFR-TKI, in EGFR T790M-Positive Non-Small Cell Lung Cancer (ID 9168)
09:30 - 16:00 | Author(s): Takashi Kohno
- Abstract
Background:
Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have shown promising efficacy in EGFR T790M-mutation-positive non-small cell lung cancer (NSCLC). However, acquired resistance to third-generation EGFR-TKIs has been reported in EGFR T790M-positive NSCLC. The mechanism of resistance to these third-generation EGFR-TKIs has not been fully elucidated. We report a case of metastatic NSCLC harboring an EGFR T790M mutation in which EGFR amplification mediated acquired resistance to TAS121, a novel third-generation EGFR-TKI.
Method:
A 68-year-old woman with metastatic lung adenocarcinoma, harboring an EGFR L858R mutation, received gefitinib in September 2013. Although the patient achieved a partial response, the tumor progressed and she was treated with 4 cycles of chemotherapy using cisplatin and pemetrexed followed by pemetrexed maintenance therapy. In April 2015, computed tomography (CT) showed disease progression (PD) with liver metastases, and re-biopsy of hepatic lesions was performed. Tumor genotyping with the PNA LNA PCR-Clamp method revealed an original mutation of EGFR L858R in exon 21 and a secondary mutation of EGFR T790M in exon 20. Tumor progression was noted after completion of one cycle of docetaxel, and she was enrolled into a phase 1 trial of TAS121 in June 2015. Although she showed a partial response to TAS121, PD was confirmed on CT, which indicated progression of liver metastases. She discontinued TAS121 and received supportive care. She died in October 2015, and an autopsy was performed. To determine the mechanism of resistance to TAS121, we performed next-generation sequencing (NGS) (NCC OncoPanel, Agilent) with post-TAS121 samples obtained from progressing liver lesions during TAS121 treatment. We also conducted fluorescence in situ hybridization (FISH) analysis for EGFR in pre-TAS121 liver lesions, post-TAS121 liver lesions, and autopsy samples from the lung and liver. The study protocol was approved by the Ethical Review Committee of the National Cancer Center Hospital.
Result:
NGS with the post-TAS121 liver samples showed EGFR amplification in the tumor cells (log2 ratio 2.2). On FISH analysis, EGFR amplification was not detected in the pre-TAS121 liver lesions (the ratio of EGFR signals to CEP signals 1.7), but was detected in the post-TAS121 liver lesions (2.1) and those obtained at autopsy (3.0). EGFR amplification was not detected in the autopsy samples of the lung lesions (1.0), which remained stable during TAS121 treatment.
Conclusion:
Our case revealed that genomic instability of the EGFR domain contributed to the development of resistance to TAS121. Further molecular analysis is warranted to understand the role of EGFR amplification in acquired resistance to third-generation EGFR-TKIs.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-010 - Identification of Mechanisms of Drug Resistance in RET-Rearranged Lung Cancer (ID 8637)
09:30 - 16:00 | Author(s): Takashi Kohno
- Abstract
Background:
Oncogenic fusions of the RET kinase gene, which was discovered by us in 1‒2% of LADCs (Kohno et al, Nat Med, 2012), have been suggested as a therapeutic target for existing tyrosine kinase inhibitors (TKIs). Actually, several clinical trials investigating RET tyrosine kinase inhibitors (TKIs) for the therapy of RET-positive LAD showed promising clinical outcome. However, the cancer inevitably acquires resistance to TKI like other driver oncogene positive LAD.
Method:
To identify a mechanism of TKI resistance in RET-driven lung cancer, we generated resistant cells to several RET-TKIs using LC-2/Ad cells that are RET-rearranged lung cancer cell lines. In addition, we established cells stably expressing RET fusion cDNA and RET-rearranged cells edited by CRISPR/Cas9, and generated resistant cells using these cells. We performed targeted sequencing covering 50 genes on a pair of resistant and pre-treatment cells. To identify the bypath track, then we performed antibody array and investigated change of mRNA expressions.
Result:
No genetic alteration was found in resistant cells by targeted sequencing. Antibody array found the activation of other tyrosine kinase, including EGFR and other HER family. Actually, the addition of the growth factors activating the kinases reduced the inhibitory effect of the TKIs. In addition, the TKI to suppress signaling of the kinase in combination with RET TKI reduced the cell viability in resistant cells.
Conclusion:
The inhibition of bypath track in combination of RET signaling could be an effective therapy for RET-rearranged lung cancer. In the meeting we plan to report the progress.
