Faculty Profiles - Togashi Yosuke

Papers - Togashi Yosuke

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Immune suppression by PD-L2 against spontaneous and treatment-related antitumor immunity. Reviewed

Tanegashima T, Togashi Y, Azuma K, Kawahara A, Ideguchi K, Sugiyama D, Kinoshita F, Akiba J, Kashiwagi E, Takeuchi A, Irie T, Tatsugami K, Hoshino T, Eto M, Nishikawa H

Clinical cancer research : an official journal of the American Association for Cancer Research 25 ( 15 ) 4808 - 4819 2019.5

PD-1⁺ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer. Reviewed International journal

Kamada T, Togashi Y, Tay C, Ha D, Sasaki A, Nakamura Y, Sato E, Fukuoka S, Tada Y, Tanaka A, Morikawa H, Kawazoe A, Kinoshita T, Shitara K, Sakaguchi S, Nishikawa H

Proceedings of the National Academy of Sciences of the United States of America 116 ( 20 ) 9999 - 10008 2019.4

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

PD-1 blockade is a cancer immunotherapy effective in various types of cancer. In a fraction of treated patients, however, it causes rapid cancer progression called hyperprogressive disease (HPD). With our observation of HPD in ∼10% of anti-PD-1 monoclonal antibody (mAb)-treated advanced gastric cancer (GC) patients, we explored how anti-PD-1 mAb caused HPD in these patients and how HPD could be treated and prevented. In the majority of GC patients, tumor-infiltrating FoxP3highCD45RA-CD4+ T cells [effector Treg (eTreg) cells], which were abundant and highly suppressive in tumors, expressed PD-1 at equivalent levels as tumor-infiltrating CD4+ or CD8+ effector/memory T cells and at much higher levels than circulating eTreg cells. Comparison of GC tissue samples before and after anti-PD-1 mAb therapy revealed that the treatment markedly increased tumor-infiltrating proliferative (Ki67+) eTreg cells in HPD patients, contrasting with their reduction in non-HPD patients. Functionally, circulating and tumor-infiltrating PD-1+ eTreg cells were highly activated, showing higher expression of CTLA-4 than PD-1- eTreg cells. PD-1 blockade significantly enhanced in vitro Treg cell suppressive activity. Similarly, in mice, genetic ablation or antibody-mediated blockade of PD-1 in Treg cells increased their proliferation and suppression of antitumor immune responses. Taken together, PD-1 blockade may facilitate the proliferation of highly suppressive PD-1+ eTreg cells in HPDs, resulting in inhibition of antitumor immunity. The presence of actively proliferating PD-1+ eTreg cells in tumors is therefore a reliable marker for HPD. Depletion of eTreg cells in tumor tissues would be effective in treating and preventing HPD in PD-1 blockade cancer immunotherapy.

DOI： 10.1073/pnas.1822001116

Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Reviewed

Togashi Y, Shitara K, Nishikawa H

Nature reviews. Clinical oncology 16 ( 6 ) 356 - 371 2019.1

Authorship：Lead author Language：English Publisher：NATURE PORTFOLIO

Regulatory T (T-reg) cells, an immunosuppressive subset of CD4(+) T cells characterized by the expression of the master transcription factor forkhead box protein P3 (FOXP3), are a component of the immune system with essential roles in maintaining self-tolerance. In addition, T-reg cells can suppress anticancer immunity, thereby hindering protective immunosurveillance of neoplasia and hampering effective antitumour immune responses in tumour-bearing hosts, thus promoting tumour development and progression. Identification of the factors that are specifically expressed in T-reg cells and/or that influence T-reg cell homeostasis and function is important to understanding cancer pathogenesis and to identifying therapeutic targets. Immune-checkpoint inhibitors (ICIs) have provided a paradigm shift in the treatment of cancer. Most immune-checkpoint molecules are expressed in T-reg cells, but the effects of ICIs on T-reg cells, and thus the contributions of these cells to treatment responses, remain unclear. Notably, evidence indicates that ICIs targeting programmed cell death 1 (PD-1) might enhance the immunosuppressive function of T-reg cells, whereas cytotoxic T lymphocyte antigen 4 (CTL A-4) inhibitors might deplete these cells. Thus, although manipulation of T-reg cells is a promising anticancer therapeutic strategy, approaches to controlling these cells require further research. Herein, we discuss novel insights into the roles of T-reg cells in cancer, which can hopefully be used to develop T-reg cell-targeted therapies and facilitate immune precision medicine.

DOI： 10.1038/s41571-019-0175-7

Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer. Reviewed International journal

Satomi Watanabe, Hidetoshi Hayashi, Koji Haratani, Shigeki Shimizu, Junko Tanizaki, Kazuko Sakai, Hisato Kawakami, Kimio Yonesaka, Junji Tsurutani, Yosuke Togashi, Kazuto Nishio, Akihiko Ito, Kazuhiko Nakagawa

Cancer science 110 ( 1 ) 52 - 60 2019.1

Language：English Publishing type：Research paper (scientific journal)

The efficacy of programmed cell death-1 (PD-1) blockade in patients with non-small cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutations has been found to be limited, but the underlying mechanisms for this poor response have remained obscure. Given that the recognition by T cells of tumor antigens presented by major histocompatibility complex class I (MHC-I) molecules is essential for an antitumor immune response, we examined the effects of EGFR tyrosine kinase inhibitors (TKIs) on MHC-I expression in NSCLC cell lines. Appropriate EGFR-TKIs increased MHC-I expression at the mRNA and cell surface protein levels in NSCLC cells positive for EGFR mutations including those with the T790M secondary mutation. Trametinib, an inhibitor of the extracellular signal-regulated kinase (ERK) kinase MEK, also increased MHC-I expression, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor buparlisib did not, suggesting that the MEK-ERK pathway mediates the down-regulation of MHC-I expression in response to EGFR activation. Immunohistochemical analysis of EGFR-mutated NSCLC specimens obtained before and after EGFR-TKI treatment also revealed down-regulation of phosphorylated forms of EGFR and ERK in association with up-regulation of MHC-I, an increased number of infiltrating CD8+ T cells, and increased PD-1 ligand 1 expression after such treatment. Our results thus suggest that mutational activation of EGFR inhibits MHC-I expression through the MEK-ERK pathway in NSCLC and thereby contributes to the poor response of such tumors to immunotherapy. Further studies are warranted to evaluate the relation between EGFR-MEK-ERK signaling in and the immune response to EGFR-mutated NSCLC. .

DOI： 10.1111/cas.13860

非小細胞肺癌において上皮成長因子受容体が変異活性化すると細胞外シグナル調節キナーゼを介して主要組織適合遺伝子複合体クラスIの発現が下方制御される(Mutational activation of the epidermal growth factor receptor down-regulates major histocompatibility complex class I expression via the extracellular signal-regulated kinase in non-small cell lung cancer)

Watanabe Satomi, Hayashi Hidetoshi, Haratani Koji, Shimizu Shigeki, Tanizaki Junko, Sakai Kazuko, Kawakami Hisato, Yonesaka Kimio, Tsurutani Junji, Togashi Yosuke, Nishio Kazuto, Ito Akihiko, Nakagawa Kazuhiko

Cancer Science 110 ( 1 ) 52 - 60 2019.1

Language：English Publisher：John Wiley & Sons Australia, Ltd

非小細胞肺癌の細胞株や患者由来検体を実験材料とし、上皮成長因子受容体(EGFR)チロシンキナーゼ阻害薬(TKI)がMHCクラスIの発現に及ぼす影響について調査した。EGFR遺伝子にT790M二次的突然変異などの変異がある細胞株を適切なEGFR-TKIで処理するとMHCクラスIのmRNA/蛋白質発現は亢進した。細胞外シグナル調節キナーゼ(ERK)キナーゼであるMEKの阻害薬で処理した場合もMHCクラスI発現が亢進したことから、EGFR活性化に応答してみられるMHCクラスI発現の下方制御はMEK-ERK経路が媒介していることが示唆された。EGFR-TKI治療を施行したEGFR変異非小細胞肺癌患者から得た検体の免疫組織化学解析からも、疾患進行後においては、リン酸化EGFRやリン酸化ERKの下方制御が、MHC-Iの上方制御、CD8+浸潤T細胞の増加、およびPD-1リガンド1発現亢進と関連していることが明らかになった。これらの結果から、非小細胞癌においてEGFRが変異活性化するとMEK-ERK経路を通じてMHCクラスI発現が阻害され、免疫療法に不応となるのに寄与することが示唆された。

Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J04765&link_issn=&doc_id=20190117540006&doc_link_id=10.1111%2Fcas.13860&url=https%3A%2F%2Fdoi.org%2F10.1111%2Fcas.13860&type=Crossref&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00002_2.gif

Targeting VEGFR2 with Ramucirumab strongly impacts effector/ activated regulatory T cells and CD8⁺ T cells in the tumor microenvironment. Reviewed International journal

Tada Y, Togashi Y, Kotani D, Kuwata T, Sato E, Kawazoe A, Doi T, Wada H, Nishikawa H, Shitara K

Journal for immunotherapy of cancer 6 ( 1 ) 106 - 106 2018.10

Authorship：Lead author Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Several studies have established a correlation between the VEGF-VEGFR2 axis and an immunosuppressive microenvironment; this immunosuppression can be overcome by anti-angiogenic reagents, such as ramucirumab (RAM). However, little is known about the immunological impact of anti-angiogenic reagents within the tumor microenvironment in human clinical samples. This study aimed at investigating the effects of RAM on the tumor microenvironmental immune status in human cancers. METHODS: We prospectively enrolled 20 patients with advanced gastric cancer (GC) who received RAM-containing chemotherapy. We obtained paired samples from peripheral blood mononuclear cells (PBMCs) and tumor-infiltrating lymphocytes (TILs) in primary tumors both pre- and post-RAM therapy to assess immune profiles by immunohistochemistry and flow cytometry. RESULTS: Within the tumor microenvironment, both PD-L1 expression and CD8+ T-cell infiltration increased after RAM-containing therapies. In addition, CD45RA-FOXP3highCD4+ cells (effector regulatory T cells [eTreg cells]) and PD-1 expression by CD8+ T cells were significantly reduced in TILs compared with PBMCs after RAM-containing therapies. Patients with partial response and longer progression-free survival had significantly higher pre-treatment eTreg frequencies in TILs than those with progressive disease. In in vitro analysis, VEGFR2 was highly expressed by eTreg cells. Further, VEGFA promoted VEGFR2+ eTreg cell proliferation, and this effect could be inhibited by RAM. CONCLUSIONS: This study suggests that the frequency of eTreg cells in TILs could be a biomarker for stratifying clinical responses to RAM-containing therapies. Further, we propose that RAM may be employed as an immuno-modulator in combination with immune checkpoint blockade.

DOI： 10.1186/s40425-018-0403-1

Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein–Barr virus status, and cancer genome alterations in metastatic gastric cancer Reviewed

Akihito Kawazoe, Kohei Shitara, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Takayuki Yoshino, Atsushi Ohtsu, Atsushi Ochiai, Yosuke Togashi, Hiroyoshi Nishikawa, Toshihiko Doi, Takeshi Kuwata

Gastric Cancer 1 - 8 2018.6

Language：English Publishing type：Research paper (scientific journal) Publisher：Springer Tokyo

Background: Recently, the U.S. Food and Drug Administration approved pembrolizumab for patients (pts) with PD-L1-positive metastatic gastric cancer (MGC) based on 22C3 immunohistochemistry (IHC) assay. However, little is known about detailed clinicopathological features of 22C3 PD-L1 expression in MGC. Patients and methods: Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression (22C3) on tumor cell (TC) or immune cell (IC) and mismatch repair (MMR) were analyzed by IHC. Epstein–Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) and cancer genome alterations were evaluated by IHC or next-generation sequencing. Results: A total of 225 pts were analyzed in this study. PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P &lt
0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P &lt
0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor. Conclusions: 22C3 PD-L1 expression in MGC was associated with distinct clinicopathological features, but was not a prognostic factor.

DOI： 10.1007/s10120-018-0843-9

Immunological impact of ramucirumab on tumor microenvironment in advanced gastric cancer. Reviewed

Togashi Yosuke, Tada Yasuko, Kotani Daisuke, Kawazoe Akihito, Doi Toshihiko, Nishikawa Hiroyoshi

https://jitc.biomedcentral.com 36 ( 5 ) 2018.2

Suppression from beyond the grave Reviewed

Yosuke Togashi, Hiroyoshi Nishikawa

NATURE IMMUNOLOGY 18 ( 12 ) 1285 - 1286 2017.12

Tumor immune microenvironment and nivolumab efficacy in EGFR mutation-positive non-small-cell lung cancer based on T790M status after disease progression during EGFR-TKI treatment Reviewed

K. Haratani, H. Hayashi, T. Tanaka, H. Kaneda, Y. Togashi, K. Sakai, K. Hayashi, S. Tomida, Y. Chiba, K. Yonesaka, Y. Nonagase, T. Takahama, J. Tanizaki, K. Tanaka, T. Yoshida, K. Tanimura, M. Takeda, H. Yoshioka, T. Ishida, T. Mitsudomi, K. Nishio, K. Nakagawa

ANNALS OF ONCOLOGY 28 ( 7 ) 1532 - 1539 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

Background: The efficacy of programmed death-1 blockade in epidermal growth factor receptor gene (EGFR) mutation-positive non-small-cell lung cancer (NSCLC) patients with different mechanisms of acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) is unknown. We retrospectively evaluated nivolumab efficacy and immune-related factors in such patients according to their status for the T790M resistance mutation of EGFR.
Patients and methods: We identified 25 patients with EGFR mutation-positive NSCLC who were treated with nivolumab after disease progression during EGFR-TKI treatment (cohort A). Programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocyte (TIL) density in tumor specimens obtained after acquisition of EGFR-TKI resistance were determined by immunohistochemistry. Whole-exome sequencing of tumor DNA was carried out to identify gene alterations. The relation of T790M status to PD-L1 expression or TIL density was also examined in an independent cohort of 60 patients (cohort B).
Results: In cohort A, median progression-free survival (PFS) was 2.1 and 1.3 months for T790M-negative and T790M-positive patients, respectively (P = 0.099; hazard ratio of 0.48 with a 95% confidence interval of 0.20-1.24). Median PFS was 2.1 and 1.3 months for patients with a PD-L1 expression level of >= 1% or <1%, respectively (P = 0.084; hazard ratio of 0.37, 95% confidence interval of 0.10-1.21). PFS tended to increase as the PD-L1 expression level increased with cutoff values of >= 10% and >= 50%. The proportion of tumors with a PD-L1 level of >= 10% or >= 50% was higher among T790M-negative patients than among T790M-positive patients of both cohorts A and B. Nivolumab responders had a significantly higher CD8(+) TIL density and nonsynonymous mutation burden.
Conclusion: T790M-negative patients with EGFR mutation-positive NSCLC are more likely to benefit from nivolumab after EGFR-TKI treatment, possibly as a result of a higher PD-L1 expression level, than are T790M-positive patients.

DOI： 10.1093/annonc/mdx183

Clinical significance of Akt2 in advanced pancreatic cancer treated with erlotinib Reviewed

Eri Banno, Yosuke Togashi, Marco A. De Velasco, Takuro Mizukami, Yu Nakamura, Masato Terashima, Kazuko Sakai, Yoshihiko Fujita, Ken Kamata, Masayuki Kitano, Masatoshi Kudo, Kazuto Nishio

INTERNATIONAL JOURNAL OF ONCOLOGY 50 ( 6 ) 2049 - 2058 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Akt2 is an isoform of Akt, and an association between Akt2 and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has been suggested in pancreatic cancer (PC) in vitro. In this study, we investigated the association between Akt2 expression as evaluated using immunohistochemistry and the outcome of patients with advanced PC who had received treatment with erlotinib (an EGFR-TKI). Although the difference was not significant, patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with erlotinib plus gemcitabine than those with low expression levels (P=0.16 and 0.19, respectively). In vitro, an Akt2-amplified PC cell line and Akt2-overexpressed cell lines exhibited resistance to anti-EGFR therapies, including erlotinib, but combined treatment with BYL719 (a PI3K inhibitor) cancelled this resistance. Our findings suggest that Akt2 might be associated with the resistance to anti-EGFR therapies, especially the use of erlotinib against PC, and that this resistance can be overcome by combined treatment with a PI3K inhibitor. Akt2 expression could become a predictive biomarker for erlotinib resistance in PC.

DOI： 10.3892/ijo.2017.3961

Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A Reviewed

Masato Chiba, Yosuke Togashi, Eri Bannno, Yoshihisa Kobayashi, Yu Nakamura, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasco, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

BMC CANCER 17 ( 1 ) 281 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) gene mutations (exon 19 deletion or exon 21 L858R) respond to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The secondary T790 M mutation in exon 20 of the EGFR gene is the most common type of acquired resistance mutation. Several reports have also shown that other secondary mutations (L747S, D761Y and T854A), while uncommon, can induce acquired resistance to first-generation EGFR-TKIs. However, little is known about the anticancer activities of second-or third-generation EGFR-TKIs.
Methods: Uncommon secondary mutations were introduced into Ba/F3 cells along with the sensitive EGFR L858R mutation (Ba/F3-L858R/L747S, Ba/F3-L858R/D761Y, and Ba/F3-L858R/T854A), and the sensitivities to various EGFR-TKIs were then investigated.
Results: Both the Ba/F3-L858R/L747S and Ba/F3-L858R/D761Y cell lines exhibited weak resistances to first-generation reversible EGFR-TKIs, while the Ba/F3-L858R/T854A cell line exhibited a strong resistance. In contrast, irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, were capable of overcoming these resistances. Western blot analyses demonstrated that gefitinib (first-generation) inhibited the phosphorylation of EGFR to a lesser extent in cells with these secondary mutations than in cells with the sensitive L858R mutation alone. In contrast, afatinib and osimertinib (second-and third-generation) inhibited the phosphorylation of EGFR in cells with these secondary mutations to a similar extent as that seen in cells with the sensitive L858R mutation alone.
Conclusions: Our experimental findings suggest that irreversible EGFR-TKIs, especially third-generation EGFR-TKIs, can be effective against uncommon secondary mutations and that switching to third-generation EGFR-TKIs could be a promising treatment strategy for patients with acquired resistance because of these uncommon secondary mutations.

DOI： 10.1186/s12885-017-3263-z

Characterization of EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib in Lung Cancer Reviewed

Yoshihisa Kobayashi, Koichi Azuma, Hiroki Nagai, Young Hak Kim, Yosuke Togashi, Yuichi Sesumi, Masato Chiba, Masaki Shimoji, Katsuaki Sato, Kenji Tomizawa, Toshiki Takemoto, Kazuto Nishio, Tetsuya Mitsudomi

MOLECULAR CANCER THERAPEUTICS 16 ( 2 ) 357 - 364 2017.2

Language：English Publishing type：Research paper (scientific journal) Publisher：AMER ASSOC CANCER RESEARCH

Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI). We previously reported that tumors with exon 18 mutations are particularly sensitive to irreversible second-generation (2G) afatinib compared with firstgeneration TKIs (1G-TKI). However, data on the mechanisms of acquired resistance to afatinib are limited. We established afatinib-resistant cells by transfecting Ba/F3 cells with common or exon 18 (G719A and Del18) mutations and subjecting them to chronic exposure to increasing concentrations of afatinib. Afatinib-resistant clones were separately established through N-ethylN-nitrosourea (ENU) mutagenesis and exposure to fixed concentrations of afatinib. Rebiopsy samples from patients whose tumors acquired resistance to afatinib were analyzed. Afatinibresistant cells with Del19, L858R, or G719A developed T790M, whereas those with Del18 acquired novel L792F mutation. ENU mutagenesis screening established 84 afatinib-resistant clones. All Del19 clones and most of the other clones acquired only T790M. However, C797S occurred in subsets of L858R, G719A, and Del18 clones. In addition, subsets of Del18 clones acquired L792F. C797S-acquired cells were sensitive to 1G erlotinib. L792F demonstrated intermediate resistance between T790M and C797S to both 1G-and 3G-TKIs, whereas L792F was the least resistant to 2G-TKIs, particularly dacomitinib. Chronic exposure of Del18-L792F cells to dacomitinib induced additional T790M. T790M was detected in one of four clinical samples. In conclusion, L792F and C797S, in addition to the major T790M, can develop in afatinib-resistant cells particularly using a low dose of afatinib, and these minor mutations appear to exhibit sensitivity to dacomitinib and erlotinib, respectively. These secondary mutations should be tested in clinical practice.

DOI： 10.1158/1535-7163.MCT-16-0407

Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies Reviewed International journal

Takuro Mizukami, Yosuke Togashi, Saeko Naruki, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Azusa Yoneshige, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Takashi Fujino, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio

Molecular Carcinogenesis 56 ( 1 ) 106 - 117 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：John Wiley and Sons Inc.

Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of &gt
5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. © 2016 Wiley Periodicals, Inc.

DOI： 10.1002/mc.22476

Significance of FGF9 gene in resistance to anti-EGFR therapies targeting colorectal cancer: A subset of colorectal cancer patients with FGF9 upregulation may be resistant to anti-EGFR therapies Reviewed

Takuro Mizukami, Yosuke Togashi, Saeko Naruki, Eri Banno, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Azusa Yoneshige, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Takashi Fujino, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio

MOLECULAR CARCINOGENESIS 56 ( 1 ) 106 - 117 2017.1

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Although fibroblast growth factor (FGF) signals are strongly associated with malignancy, limited information is available regarding the role of the FGF9 signal in colorectal cancer (CRC). In this study, we investigated the frequency of FGF9 amplification in CRC clinical specimens and the association between the FGF9 gene and resistance to anti-EGFR therapies. In clinical samples, an FGF9 copy number gain of 5 copies was observed at a frequency of 8/145 (5.5%) and tended to be related to wild-type KRAS (7/96, 7.3%). Furthermore, FGF9 amplification was not observed in any of the samples from the 15 responders to anti-EGFR therapies but was observed in one sample from the seven non-responders with wild-type KRAS, and two samples from non-responders also had high FGF9 mRNA expression levels. FGF9 amplification was validated using a fluorescence in situ hybridization (FISH) analysis, and FGF9-amplified sections showed readily detectable signals originating from FGF9 protein when examined using immunohistochemistry. In both the in vitro and in vivo experiments using FGF9-overexpressing CRC cell lines, FGF9 overexpression induced strong resistance to anti-EGFR therapies via the enforced FGFR signal, and this resistance was cancelled by the application of an FGFR inhibitor. Considering these results, the FGF9 gene may play an important role in resistance to anti-EGFR therapies in patients with CRC, and such resistance might be overcome by combined treatment with an anti-FGFR inhibitor. These findings strongly encourage the development of FGFR-targeted therapy for CRC patients with FGF9 gene upregulation. (c) 2016 Wiley Periodicals, Inc.

DOI： 10.1002/mc.22476

Regulatory T Cells: Molecular and Cellular Basis for Immunoregulation Reviewed

Yosuke Togashi, Hiroyoshi Nishikawa

EMERGING CONCEPTS TARGETING IMMUNE CHECKPOINTS IN CANCER AND AUTOIMMUNITY 410 3 - 27 2017

Language：English Publishing type：Part of collection (book) Publisher：SPRINGER INTERNATIONAL PUBLISHING AG

CD4(+) regulatory T cells (Tregs) are a highly immune-suppressive subset of CD4(+) T cells, characterized by expression of the master regulatory transcription factor FOXP3. Tregs are proven to play central roles in the maintenance of self-tolerance in healthy individuals. Tregs are involved in maintaining immune homeostasis: they protect hosts from developing autoimmune diseases and allergy, whereas in malignancies, they promote tumor progression by suppressing anti-tumor immunity. Elucidating factors influencing Treg homeostasis and function have important implications for understanding disease pathogenesis and identifying therapeutic opportunities. Thus, the manipulating Tregs for up-or down-regulation of their suppressive function is a new therapeutic strategy for treating various diseases including autoimmune disorders and cancer. This review will focus on recent advances in how Tregs integrate extracellular and intracellular signals to control their survival and stability. Deeper mechanistic understanding of disease-specific Treg development, maintenance, and function could make disease-specific Treg-targeted therapy more effective, resulting in an increase of efficacy and decrease of side effects related to manipulating Tregs.

DOI： 10.1007/82_2017_58

MEK inhibitors against MET-amplified non-small cell lung cancer Reviewed

Masato Chiba, Yosuke Togashi, Shuta Tomida, Hiroshi Mizuuchi, Yu Nakamura, Eri Banno, Hidetoshi Hayashi, Masato Terashima, Marco A. De Velasc, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

INTERNATIONAL JOURNAL OF ONCOLOGY 49 ( 6 ) 2236 - 2244 2016.12

Language：English Publishing type：Research paper (scientific journal) Publisher：SPANDIDOS PUBL LTD

Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFRmutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

DOI： 10.3892/ijo.2016.3736

FGFR gene alterations in lung squamous cell carcinoma are potential targets for the multikinase inhibitor nintedanib Reviewed

Masaaki Hibi, Hiroyasu Kaneda, Junko Tanizaki, Kazuko Sakai, Yosuke Togashi, Masato Terashima, Marco Antonio De Velasco, Yoshihiko Fujita, Eri Banno, Yu Nakamura, Masayuki Takeda, Akihiko Ito, Tetsuya Mitsudomi, Kazuhiko Nakagawa, Isamu Okamoto, Kazuto Nishio

CANCER SCIENCE 107 ( 11 ) 1667 - 1676 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Fibroblast growth factor receptor (FGFR) gene alterations are relatively frequent in lung squamous cell carcinoma (LSCC) and are a potential targets for therapy with FGFR inhibitors. However, little is known regarding the clinicopathologic features associated with FGFR alterations. The angiokinase inhibitor nintedanib has shown promising activity in clinical trials for non-small cell lung cancer. We have now applied next-generation sequencing (NGS) to characterize FGFR alterations in LSCC patients as well as examined the antitumor activity of nintedanib in LSCC cell lines positive for FGFR1 copy number gain (CNG). The effects of nintedanib on the proliferation of and FGFR signaling in LSCC cell lines were examined invitro, and its effects on tumor formation were examined invivo. A total of 75 clinical LSCC specimens were screened for FGFR alterations by NGS. Nintedanib inhibited the proliferation of FGFR1 CNG-positive LSCC cell lines in association with attenuation of the FGFR1-ERK signaling pathway invitro and invivo. FGFR1 CNG (10.7%), FGFR1 mutation (2.7%), FGFR2 mutation (2.7%), FGFR4 mutation (5.3%), and FGFR3 fusion (1.3%) were detected in LSCC specimens by NGS. Clinicopathologic features did not differ between LSCC patients positive or negative for FGFR alterations. However, among the 36 patients with disease recurrence after surgery, prognosis was significantly worse for those harboring FGFR alterations. Screening for FGFR alterations by NGS warrants further study as a means to identify patients with LSCC recurrence after surgery who might benefit from nintedanib therapy.

DOI： 10.1111/cas.13071

Case report: Durable response to afatinib in a patient with lung cancer harboring two uncommon mutations of EGFR and a KRAS mutation Reviewed

Junko Tanizaki, Eri Banno, Yosuke Togashi, Hidetoshi Hayashi, Kazuko Sakai, Masayuki Takeda, Hiroyasu Kaneda, Kazuto Nishio, Kazuhiko Nakagawa

LUNG CANCER 101 11 - 15 2016.11

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER IRELAND LTD

Comprehensive genomic profiling for non-small cell lung cancer (NSCLC) is likely to identify more patients with rare genetic alterations including uncommon epidermal growth factor receptor gene (EGFR) mutations. It remains unclear how such patients should be treated, however. We here report a case of NSCLC positive for two uncommon mutations of EGFR and a KRAS mutation, including its treatment with the second-generation EGFR tyrosine kinase inhibitor (TKI) afatinib. Tumor specimen obtained by a NSCLC patient with no smoking history was analyzed by next-generation sequencing. Comprehensive genomic profiling revealed that the patient harbored the EGFR mutations G719C and S768I as well as the E49K mutation of KRAS. Treatment with afatinib was clinically effective as confirmed by PET-CT scans of bone metastases and by a marked decrease in the serum concentration of carcinoembryonic antigen. Afatinib was the most effective among seven EGFR-TKIs tested in inhibiting the growth of Ba/F3 cells expressing EGFR(S768I), showing an efficacy similar to that apparent with cells expressing the common EGFR mutant L858R, whereas first- and third-generation EGFR-TKIs were markedly less effective against EGFR(S7681) than against EGFR(L858R). These data suggest that EGFR-TKIs differ in their activity toward cells expressing EGFR(S7681) in vitro. Consistently, afatinib was clinically effective for the treatment of NSCLC harboring G719C and S768I mutations of EGFR. Further studies are warranted to determine the most appropriate EGFR-TKI for treatment of NSCLC harboring uncommon EGFR mutations. (C) 2016 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2016.09.001

Sensitivities to various epidermal growth factor receptor-tyrosine kinase inhibitors of uncommon epidermal growth factor receptor mutations L861Q and S768I: What is the optimal epidermal growth factor receptor-tyrosine kinase inhibitor? Reviewed

Eri Banno, Yosuke Togashi, Yu Nakamura, Masato Chiba, Yoshihisa Kobayashi, Hidetoshi Hayashi, Masato Terashima, Marco A. de Velasco, Kazuko Sakai, Yoshihiko Fujita, Tetsuya Mitsudomi, Kazuto Nishio

CANCER SCIENCE 107 ( 8 ) 1134 - 1140 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：WILEY-BLACKWELL

Most patients with non-small cell lung cancer (NSCLC) harboring common epidermal growth factor receptor (EGFR) mutations, such as deletions in exon 19 or the L858R mutation in exon 21, respond dramatically to EGFR tyrosine kinase inhibitors (EGFR-TKI), and their sensitivities to various EGFR-TKI have been well characterized. Our previous article showed the in vitro sensitivities of EGFR exon 18 mutations to EGFR-TKI, but little information regarding the sensitivities of other uncommon EGFR mutations is available. First, stable transfectant Ba/F3 cell lines harboring EGFR L858R (Ba/F3-L858R), L861Q (Ba/F3-L861Q) or S768I (Ba/F3-S768I) mutations were created and their drug sensitivities to various EGFR-TKI were examined. Both the Ba/F3-L861Q and Ba/F3-S768I cell lines were less sensitive to erlotinib, compared with the Ba/F3-L858R cell line, but their sensitivities to afatinib were similar to that of the Ba/F3-L858R cell line. The Ba/F3-L861Q cell line was similarly sensitive and the Ba/F3-S768I cell line was less sensitive to osimertinib, compared with the Ba/F3-L858R cell line. The results of western blot analyses were consistent with these sensitivities. Next, similar experiments were also performed using the KYSE270 (L861Q) and KYSE 450 (S768I) cell lines, and their results were compatible with those of the transfectant Ba/F3 cell lines. Our findings suggest that NSCLC harboring the EGFR L861Q mutation might be sensitive to afatinib or osimertinib and that NSCLC harboring the EGFR S768I mutation might be sensitive to afatinib. Overall, afatinib might be the optimal EGFR-TKI against these uncommon EGFR mutations.

DOI： 10.1111/cas.12980

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