Faculty Profiles - ICHIHARA Eiki

Papers - ICHIHARA Eiki

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Effect of Vandetanib on Lung Tumorigenesis in Transgenic Mice Carrying an Activating Egfr Gene Mutation.

Masahiro Osawa, Kadoaki Ohashi, Toshio Kubo, Eiki Ichihara, Saburo Takata, Nagio Takigawa, Minoru Takata, Mitsune Tanimoto, Katsuyuki Kiura

Acta medica Okayama 70 ( 4 ) 243 - 53 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Vandetanib (ZactimaTM) is a novel, orally available inhibitor of both vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor receptor (EGFR) tyrosine kinase. In the present study, a line of transgenic mice with a mouse Egfr gene mutation (delE748-A752) corresponding to a human EGFR mutation (delE746-A750) was established. The transgenic mice developed atypical adenomatous hyperplasia to adenocarcinoma of the lung at around 5 weeks of age and died of lung tumors at approximately 17 weeks of age. In the mice treated with vandetanib (6mg/kg/day), these lung tumors disappeared and the phosphorylations of EGFR and VEGFR-2 were reduced in lung tissues to levels comparable to those of non-transgenic control mice. The median overall survival time of the transgenic mice was 28 weeks in the vandetanib-treated group and 17 weeks in the vehicle-treated group. Vandetanib significantly prolonged the survival of the transgenic mice (log-rank test, p＜ 0.01); resistance to vandetanib occurred at 20 weeks of age and the animals died from their lung tumors at about 28 weeks of age. These data suggest that vandetanib could suppress the progression of tumors harboring an activating EGFR mutation.

EGFR Fusions as Novel Therapeutic Targets in Lung Cancer. International journal

Kartik Konduri, Jean-Nicolas Gallant, Young Kwang Chae, Francis J Giles, Barbara J Gitlitz, Kyle Gowen, Eiki Ichihara, Taofeek K Owonikoko, Vijay Peddareddigari, Suresh S Ramalingam, Satyanarayan K Reddy, Beth Eaby-Sandy, Tiziana Vavalà, Andrew Whiteley, Heidi Chen, Yingjun Yan, Jonathan H Sheehan, Jens Meiler, Deborah Morosini, Jeffrey S Ross, Philip J Stephens, Vincent A Miller, Siraj M Ali, Christine M Lovly

Cancer discovery 6 ( 6 ) 601 - 11 2016.6

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

UNLABELLED: Here, we report that novel epidermal growth factor receptor (EGFR) gene fusions comprising the N-terminal of EGFR linked to various fusion partners, most commonly RAD51, are recurrent in lung cancer. We describe five patients with metastatic lung cancer whose tumors harbored EGFR fusions, four of whom were treated with EGFR tyrosine kinase inhibitors (TKI) with documented antitumor responses. In vitro, EGFR-RAD51 fusions are oncogenic and can be therapeutically targeted with available EGFR TKIs and therapeutic antibodies. These results support the dependence of EGFR-rearranged tumors on EGFR-mediated signaling and suggest several therapeutic strategies for patients whose tumors harbor this novel alteration. SIGNIFICANCE: We report for the first time the identification and therapeutic targeting of EGFR C-terminal fusions in patients with lung cancer and document responses to the EGFR inhibitor erlotinib in 4 patients whose tumors harbored EGFR fusions. Findings from these studies will be immediately translatable to the clinic, as there are already several approved EGFR inhibitors. Cancer Discov; 6(6); 601-11. ©2016 AACR.See related commentary by Paik, p. 574This article is highlighted in the In This Issue feature, p. 561.

DOI： 10.1158/2159-8290.CD-16-0075

Non-Small Cell Lung Cancer Cells Acquire Resistance to the ALK Inhibitor Alectinib by Activating Alternative Receptor Tyrosine Kinases. International journal

Hideko Isozaki, Eiki Ichihara, Nagio Takigawa, Kadoaki Ohashi, Nobuaki Ochi, Masayuki Yasugi, Takashi Ninomiya, Hiromichi Yamane, Katsuyuki Hotta, Katsuya Sakai, Kunio Matsumoto, Shinobu Hosokawa, Akihiro Bessho, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

Cancer research 76 ( 6 ) 1506 - 16 2016.3

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

Crizotinib is the standard of care for advanced non-small cell lung cancer (NSCLC) patients harboring the anaplastic lymphoma kinase (ALK) fusion gene, but resistance invariably develops. Unlike crizotinib, alectinib is a selective ALK tyrosine kinase inhibitor (TKI) with more potent antitumor effects and a favorable toxicity profile, even in crizotinib-resistant cases. However, acquired resistance to alectinib, as for other TKIs, remains a limitation of its efficacy. Therefore, we investigated the mechanisms by which human NSCLC cells acquire resistance to alectinib. We established two alectinib-resistant cell lines that did not harbor the secondary ALK mutations frequently occurring in crizotinib-resistant cells. One cell line lost the EML4-ALK fusion gene, but exhibited increased activation of insulin-like growth factor-1 receptor (IGF1R) and human epidermal growth factor receptor 3 (HER3), and overexpressed the HER3 ligand neuregulin 1. Accordingly, pharmacologic inhibition of IGF1R and HER3 signaling overcame resistance to alectinib in this cell line. The second alectinib-resistant cell line displayed stimulated HGF autocrine signaling that promoted MET activation and remained sensitive to crizotinib treatment. Taken together, our findings reveal two novel mechanisms underlying alectinib resistance that are caused by the activation of alternative tyrosine kinase receptors rather than by secondary ALK mutations. These studies may guide the development of comprehensive treatment strategies that take into consideration the various approaches ALK-positive lung tumors use to withstand therapeutic insult.

DOI： 10.1158/0008-5472.CAN-15-1010

インターロイキン-6はEGFRに変異を有する進行性のNSCLC患者におけるゲフィチニブの治療効果に関する価値のある予測マーカである(Interleukin6 is a Valuable Predictive Marker for Therapeutic Effect of Gefitinib in Patients with Advanced NSCLC Harboring EGFR mutations)

Tamura Tomoki, Hotta Katsuyuki, Kato Yuka, Gotoda Hiroko, Tanaka Takehiro, Ichimura Koichi, Kubo Toshio, Ohashi Kadoaki, Ichihara Eiki, Kiura Katsuyuki

日本呼吸器学会誌 5 ( 増刊 ) 373 - 373 2016.3

Short-term low-volume hydration in cisplatin-based chemotherapy for patients with lung cancer: the second prospective feasibility study in the Okayama Lung Cancer Study Group Trial 1201.

Kiichiro Ninomiya, Katsuyuki Hotta, Akiko Hisamoto-Sato, Eiki Ichihara, Hiroko Gotoda, Daisuke Morichika, Tomoki Tamura, Hiroe Kayatani, Daisuke Minami, Toshio Kubo, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

International journal of clinical oncology 21 ( 1 ) 81 - 7 2016.2

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER JAPAN KK

OBJECTIVE: We previously reported the feasibility of short-term low-volume hydration in patients with advanced lung cancer who received cisplatin-based chemotherapy (Jpn J Clin Oncol 2013). We sought to determine the clinical usefulness of a more convenient hydration method, evaluating the safety and efficacy of shorter-term and lower-volume hydration. METHOD: Chemonaïve patients with advanced lung cancer who were ≤ 75 years and reserved an adequate renal function for cisplatin use (≥ 60 mg/m(2)) were eligible. An intravenously administered hydration of 1700 ml in ~3.5 h with 1500 ml of orally administered hydration was investigated. The primary endpoint was the proportion of patients without grade 2 or worse renal toxicity in the first cycle. RESULTS: A total of 45 patients were registered, all of whom were evaluable for renal toxicity. The median baseline creatinine score was 0.70 mg/dl, and the median cisplatin dose on day 1 was 75 mg/m(2). In the first cycle, one patient (2 %) developed grade 2 creatinine toxicity, and thus, the proportion of patients with less than grade 2 was 98 % (the lower limit of 95 % confidence interval; 93 %), which met the primary endpoint. Five patients (11 %) had grade 1 or greater nephrotoxicity, three of whom successfully recovered. The objective response rate was 24 % and median progression-free survival 5.8 months. CONCLUSION: This prospective study demonstrated the safety and efficacy of shorter-term lower-volume hydration.

DOI： 10.1007/s10147-015-0860-1

Short-term low-volume hydration in cisplatin-based chemotherapy: a feasibility study in lung cancer (OLCSG1201)

Kiichiro Ninomiya, Katsuyuki Hotta, Hiroko Gotoda, Daisuke Morichika, Eiki Ichihara, Akiko Sato, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

ANNALS OF ONCOLOGY 26 80 - 80 2015.11

RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. International journal

Gorjan Hrustanovic, Victor Olivas, Evangelos Pazarentzos, Asmin Tulpule, Saurabh Asthana, Collin M Blakely, Ross A Okimoto, Luping Lin, Dana S Neel, Amit Sabnis, Jennifer Flanagan, Elton Chan, Marileila Varella-Garcia, Dara L Aisner, Aria Vaishnavi, Sai-Hong I Ou, Eric A Collisson, Eiki Ichihara, Philip C Mack, Christine M Lovly, Niki Karachaliou, Rafael Rosell, Jonathan W Riess, Robert C Doebele, Trever G Bivona

Nature medicine 21 ( 9 ) 1038 - 47 2015.9

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.

DOI： 10.1038/nm.3930

Impact of body surface area on survival in EGFR-mutant non-small cell lung cancer patients treated with gefitinib monotherapy: observational study of the Okayama Lung Cancer Study Group 0703. International journal

Kenichiro Kudo, Katsuyuki Hotta, Eiki Ichihara, Hiroshige Yoshioka, Kei Kunimasa, Kazuya Tsubouchi, Masahiro Iwasaku, Yuka Kato, Isao Oze, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Cancer chemotherapy and pharmacology 76 ( 2 ) 251 - 6 2015.8

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

BACKGROUND: The approved dose of gefitinib is fixed, without adjustment for physical size. We demonstrated previously that its efficacy was affected by body surface area (BSA) in patients with EGFR-mutant non-small cell lung cancer (NSCLC). To validate these observations, we assessed the association between BSA and the efficacy of gefitinib using a different patient cohort. METHODS: Prospective cohort data from 115 NSCLC patients with EGFR-mutant tumours, who received gefitinib monotherapy between 2007 and 2012, were analysed. RESULTS: Gefitinib was less effective in individuals with a high BSA (≥1.5 m(2)) in EGFR-mutant NSCLC compared with those with a low BSA (<1.5 m(2)). The median progression-free survival (PFS) in the high- and low-BSA groups was 4.2 and 8.5 months, respectively, although there was no difference in survival among the whole NSCLC cohort. Multivariate analysis also showed a significant effect of BSA on PFS (hazard ratio 1.72; 95 % confidence interval 1.08-2.74; p = 0.021). Sensitivity analysis revealed that the use of the BSA cut-off level around 1.50 m(2) was robust for detecting subpopulations that would benefit less from gefitinib monotherapy. CONCLUSION: We found in the prospective cohort data that BSA could affect the efficacy of gefitinib monotherapy in patients with EGFR-mutant NSCLC, suggesting that BSA-based dose setting of gefitinib monotherapy might be further investigated, despite the fact that no molecular-targeted agent described to date undergoes dose adjustment according to BSA.

DOI： 10.1007/s00280-015-2789-5

Shades of T790M: Intratumor Heterogeneity in EGFR-Mutant Lung Cancer. International journal

Eiki Ichihara, Christine M Lovly

Cancer discovery 5 ( 7 ) 694 - 6 2015.7

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

In the setting of recent exciting clinical results and numerous ongoing trials, Piotrowska and colleagues explore mechanisms of acquired resistance to the mutant-specific EGFR inhibitor rociletinib, and demonstrate that loss of T790M, EGFR amplification, and small-cell transformation are all clinically relevant mechanisms of drug resistance. The authors provide a new paradigm for using quantitative assessment of the EGFR T790M:activation mutation allele frequency ratio to prognosticate responses to rociletinib and also demonstrate that plasma-based assessments of circulating tumor DNA can be used to monitor drug response and the emergence of drug resistance.

DOI： 10.1158/2159-8290.CD-15-0616

Acquired Resistance to the Mutant-Selective EGFR Inhibitor AZD9291 Is Associated with Increased Dependence on RAS Signaling in Preclinical Models. International journal

Catherine A Eberlein, Daniel Stetson, Aleksandra A Markovets, Katherine J Al-Kadhimi, Zhongwu Lai, Paul R Fisher, Catherine B Meador, Paula Spitzler, Eiki Ichihara, Sarah J Ross, Miika J Ahdesmaki, Ambar Ahmed, Laura E Ratcliffe, Elizabeth L Christey O'Brien, Claire H Barnes, Henry Brown, Paul D Smith, Jonathan R Dry, Garry Beran, Kenneth S Thress, Brian Dougherty, William Pao, Darren A E Cross

Cancer research 75 ( 12 ) 2489 - 500 2015.6

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

Resistance to targeted EGFR inhibitors is likely to develop in EGFR-mutant lung cancers. Early identification of innate or acquired resistance mechanisms to these agents is essential to direct development of future therapies. We describe the detection of heterogeneous mechanisms of resistance within populations of EGFR-mutant cells (PC9 and/or NCI-H1975) with acquired resistance to current and newly developed EGFR tyrosine kinase inhibitors, including AZD9291. We report the detection of NRAS mutations, including a novel E63K mutation, and a gain of copy number of WT NRAS or WT KRAS in cell populations resistant to gefitinib, afatinib, WZ4002, or AZD9291. Compared with parental cells, a number of resistant cell populations were more sensitive to inhibition by the MEK inhibitor selumetinib (AZD6244; ARRY-142886) when treated in combination with the originating EGFR inhibitor. In vitro, a combination of AZD9291 with selumetinib prevented emergence of resistance in PC9 cells and delayed resistance in NCI-H1975 cells. In vivo, concomitant dosing of AZD9291 with selumetinib caused regression of AZD9291-resistant tumors in an EGFRm/T790M transgenic model. Our data support the use of a combination of AZD9291 with a MEK inhibitor to delay or prevent resistance to AZD9291 in EGFRm and/or EGFRm/T790M tumors. Furthermore, these findings suggest that NRAS modifications in tumor samples from patients who have progressed on current or EGFR inhibitors in development may support subsequent treatment with a combination of EGFR and MEK inhibition.

DOI： 10.1158/0008-5472.CAN-14-3167

Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. International journal

Eiki Ichihara, Katsuyuki Hotta, Naoyuki Nogami, Shoichi Kuyama, Daizo Kishino, Masanori Fujii, Toshiyuki Kozuki, Masahiro Tabata, Daijiro Harada, Kenichi Chikamori, Keisuke Aoe, Hiroshi Ueoka, Shinobu Hosokawa, Akihiro Bessho, Akiko Hisamoto-Sato, Toshio Kubo, Isao Oze, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 10 ( 3 ) 486 - 91 2015.3

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

PURPOSE: Whether bevacizumab enhances the effect of the epidermal growth factor receptor (EGFR) inhibitor gefitinib on EGFR mutant non-small cell lung cancers (NSCLCs) remains unknown. We conducted a phase II trial to investigate the efficacy and safety of gefitinib when combined with bevacizumab as first-line therapy in patients with advanced NSCLC harboring EGFR gene mutations. METHODS: In this trial, 42 patients with a performance status of 0 to 2 received gefitinib (250 mg/d) and bevacizumab (15 mg/kg, every 3 weeks). The primary end point of this study was the 1-year progression-free survival (PFS) rate. We assumed that a 1-year PFS rate of 55% would indicate potential usefulness and that a 1-year PFS rate of 40% would constitute the lower limit of interest. RESULTS: Forty-two patients were enrolled in the study with a median age of 73 (range 42-86) years. Activating EGFR gene mutations included exon 19 deletion (57%) and L858R point mutations in exon 21 (38%). The objective response rate was 73.8% and included two complete responses. The 1-year PFS rate and median PFS time were 56.7% (95% confidence interval [CI] 39.9-70.5) and 14.4 months (95% CI 10.1-19.2), respectively. The median PFS differed significantly between EGFR exon 19 deletion and the L858R point mutation (18.0 versus 9.4 months, respectively; p = 0.006). The median overall survival had not yet been reached. Severe adverse events included grade 3 skin rash (15%), hypertension (17%), aspartate transaminase/alanine aminotransferase elevation (17%), proteinuria (7%), intracranial hemorrhage (2%), and grade 4 perforation of the digestive tract (2%). There were no treatment-related deaths. CONCLUSION: Gefitinib in combination with bevacizumab as first-line therapy seems to be a favorable and well-tolerated treatment for patients with advanced NSCLC with activating EGFR gene mutations, especially those with EGFR exon 19 deletion mutations, although the primary end point was not met because the lower limit of the CI was less than 40%.

DOI： 10.1097/JTO.0000000000000434

活性化型の上皮増殖因子受容体(EGFR)変異を有する肺がん細胞における低用量アファチニブとセツキシマブの併用療法に対するベバシズマブの効果(The impact of bevacizumab on combination low-dose afatinib and cetuximab therapy in lung cancer cells harboring activated EGFR mutations)

Kudo Kenichiro, Ohashi Kadoaki, Ichihara Eiki, Kubo Hisao, Minami Daisuke, Hisamoto Akiko, Hotta Katsuyuki, Tanimoto Mitsune, Kiura Katsuyuki

日本呼吸器学会誌 4 ( 増刊 ) 348 - 348 2015.3

A new human lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. International journal

Hideko Isozaki, Masayuki Yasugi, Nagio Takigawa, Katsuyuki Hotta, Eiki Ichihara, Akihiko Taniguchi, Shinichi Toyooka, Shinsuke Hashida, Toshiaki Sendo, Mitsune Tanimoto, Katsuyuki Kiura

Japanese journal of clinical oncology 44 ( 10 ) 963 - 8 2014.10

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

OBJECTIVE: The echinoderm microtubule associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) fusion gene was identified in patients with non-small cell lung cancer. To the best of our knowledge, there are only three cell lines harboring the EML4-ALK fusion gene, which have contributed to the development of therapeutic strategies. Therefore, we tried to establish a new lung cancer cell line harboring EML4-ALK. METHODS: A 61-year-old Japanese female presented with chest discomfort. She was diagnosed with left lung adenocarcinoma with T4N3M1 Stage IV. Although she was treated with chemotherapy, her disease progressed with massive pleural effusion. Because the EML4-ALK rearrangement was found in a biopsied specimen using fluorescence in situ hybridization, she was treated with crizotinib. She did well for 3 months. RESULTS: Tumor cells were obtained from the malignant pleural effusion before treatment with crizotinib. Cells continued to proliferate substantially for several weeks. The cell line was designated ABC-11. The EML4-ALK fusion protein and genes were identified in ABC-11 cells using fluorescence in situ hybridization and immunohistochemistry, respectively. ABC-11 cells were sensitive to crizotinib and next-generation ALK inhibitors (ceritinib and AP26113), as determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Phosphorylated ALK protein and its downstream signaling were suppressed by treatment with crizotinib in western blotting. Furthermore, we could transplant ABC-11 cells subcutaneously into BALB/c nu/nu mice. CONCLUSIONS: We successfully established a new lung adenocarcinoma cell line harboring the EML4-ALK fusion gene. This cell line could contribute to future research of EML4-ALK-positive lung cancer both in vivo and in vitro.

DOI： 10.1093/jjco/hyu110

AZD9291, an irreversible EGFR TKI, overcomes T790M-mediated resistance to EGFR inhibitors in lung cancer. International journal

Darren A E Cross, Susan E Ashton, Serban Ghiorghiu, Cath Eberlein, Caroline A Nebhan, Paula J Spitzler, Jonathon P Orme, M Raymond V Finlay, Richard A Ward, Martine J Mellor, Gareth Hughes, Amar Rahi, Vivien N Jacobs, Monica Red Brewer, Eiki Ichihara, Jing Sun, Hailing Jin, Peter Ballard, Katherine Al-Kadhimi, Rachel Rowlinson, Teresa Klinowska, Graham H P Richmond, Mireille Cantarini, Dong-Wan Kim, Malcolm R Ranson, William Pao

Cancer discovery 4 ( 9 ) 1046 - 61 2014.9

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

UNLABELLED: First-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provide significant clinical benefit in patients with advanced EGFR-mutant (EGFRm(+)) non-small cell lung cancer (NSCLC). Patients ultimately develop disease progression, often driven by acquisition of a second T790M EGFR TKI resistance mutation. AZD9291 is a novel oral, potent, and selective third-generation irreversible inhibitor of both EGFRm(+) sensitizing and T790M resistance mutants that spares wild-type EGFR. This mono-anilino-pyrimidine compound is structurally distinct from other third-generation EGFR TKIs and offers a pharmacologically differentiated profile from earlier generation EGFR TKIs. Preclinically, the drug potently inhibits signaling pathways and cellular growth in both EGFRm(+) and EGFRm(+)/T790M(+) mutant cell lines in vitro, with lower activity against wild-type EGFR lines, translating into profound and sustained tumor regression in EGFR-mutant tumor xenograft and transgenic models. The treatment of 2 patients with advanced EGFRm(+) T790M(+) NSCLC is described as proof of principle. SIGNIFICANCE: We report the development of a novel structurally distinct third-generation EGFR TKI, AZD9291, that irreversibly and selectively targets both sensitizing and resistant T790M(+) mutant EGFR while harboring less activity toward wild-type EGFR. AZD9291 is showing promising responses in a phase I trial even at the first-dose level, with first published clinical proof-of-principle validation being presented.

DOI： 10.1158/2159-8290.CD-14-0337

Everolimus prolonged survival in transgenic mice with EGFR-driven lung tumors. International journal

Masayuki Yasugi, Nagio Takigawa, Nobuaki Ochi, Kadoaki Ohashi, Daijiro Harada, Takashi Ninomiya, Toshi Murakami, Yoshihiro Honda, Eiki Ichihara, Mitsune Tanimoto, Katsuyuki Kiura

Experimental cell research 326 ( 2 ) 201 - 9 2014.8

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

Everolimus is an orally administered mTOR inhibitor. The effect, and mechanism of action, of everolimus on lung cancers with an epidermal growth factor receptor (EGFR) mutation remain unclear. Four gefitinib-sensitive and -resistant cell lines were used in the present work. Growth inhibition was determined using the MTT assay. Transgenic mice carrying the EGFR L858R mutation were treated with everolimus (10 mg/kg/day), or vehicle alone, from 5 to 20 weeks of age, and were then sacrificed. To evaluate the efficacy of everolimus in prolonging survival, everolimus (10 mg/kg/day) or vehicle was administered from 5 weeks of age. The four cell lines were similarly sensitive to everolimus. Expression of phosphorylated (p) mTOR and pS6 were suppressed upon treatment with everolimus in vitro, whereas the pAKT level increased. The numbers of lung tumors with a long axis exceeding 1mm in the everolimus-treated and control groups were 1.9 ± 0.9 and 9.4 ± 3.2 (t-test, p<0.001), respectively. pS6 was suppressed during eve r olimus treatment. Although apoptosis and autophagy were not induced in everolimus-treated EGFR transgenic mice, angiogenesis was suppressed. The median survival time in the everolimus-treated group (58.0 weeks) was significantly longer than that in the control group (31.2 weeks) (logrank test, p<0.001). These findings suggest that everolimus had an indirect effect on tumor formation by inhibiting angiogenesis and might be effective to treat lung tumors induced by an activating EGFR gene mutation.

DOI： 10.1016/j.yexcr.2014.04.012

Factor associated with failure to administer subsequent treatment after progression in the first-line chemotherapy in EGFR-mutant non-small cell lung cancer: Okayama Lung Cancer Study Group experience. International journal

Yuka Kato, Katsuyuki Hotta, Nagio Takigawa, Naoyuki Nogami, Toshiyuki Kozuki, Akiko Sato, Eiki Ichihara, Kenichiro Kudo, Isao Oze, Masahiro Tabata, Tetsu Shinkai, Mitsune Tanimoto, Katsuyuki Kiura

Cancer chemotherapy and pharmacology 73 ( 5 ) 943 - 50 2014.5

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

PURPOSE: Early administration of both epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) monotherapy and cytotoxic chemotherapy is crucial for non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. We investigated the effect of first-line administration of these therapies on subsequent therapy in NSCLC patients. METHODS: This study enrolled 63 consecutive patients with advanced EGFR-mutant NSCLC and good performance status (PS) and who underwent first-line EGFR-TKI therapy or standard cytotoxic chemotherapy and then had progressive disease, from 2007 to 2011. The ability of each patient to receive the other therapy after first-line treatment failure was assessed. RESULTS: In the first-line setting, 23 and 40 patients received EGFR-TKI therapy and cytotoxic chemotherapy, respectively. At relapse, the EGFR-TKI therapy group showed more frequent PS deterioration (p = 0.042) and greater likelihood of symptomatic central nervous system (CNS) relapse (p = 0.093) compared with the cytotoxic chemotherapy group. Nine (39 %) of 23 patients initially receiving EGFR-TKI therapy could not receive standard cytotoxic therapy after progression mainly due to symptomatic CNS relapse. Only one (3 %) of 40 initially treated with cytotoxic chemotherapy failed to receive subsequent EGFR-TKI therapy (p < 0.001). Multivariate analysis revealed a correlation between the first-line therapy and the failure to switch to the other therapy after disease progression (OR 48.605, p = 0.005). CONCLUSION: In this study, patients who could not receive both EGFR-TKI therapy and cytotoxic chemotherapy in the early-line setting were included more in the first-line EGFR-TKI group, suggesting a potential risk associated with missing the timing of administration of subsequent therapy. Further investigation is warranted to detect their pretreatment clinical or molecular characteristics for development of a new treatment strategy specific for such subpopulation.

DOI： 10.1007/s00280-014-2425-9

Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer. International journal

Nobuaki Ochi, Nagio Takigawa, Daijiro Harada, Masayuki Yasugi, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Mitsune Tanimoto, Katsuyuki Kiura

Experimental cell research 322 ( 1 ) 168 - 77 2014.3

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

To study epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) resistance mechanisms, we established a novel gefitinib-resistant lung cancer cell line derived from an EGFR-mutant non-small cell lung cancer cell line (PC-9) pretreated with 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (designated PC9-GR). We found that gefitinib substantially suppressed the EGFR signaling pathway, whereas ERK was reactivated after several hours in PC9-GR but not in PC-9. The combination of gefitinib with ERK inhibition (by U0126) restored gefitinib susceptibility in PC9-GR, but PI3K-Akt inhibition with LY294002 did not. Although the levels of phosphorylated Src were up-regulated simultaneously with ERK reactivation, neither ERK suppression using U0126 nor an ERK-specific siRNA induced Src phosphorylation. Furthermore, dual inhibition of EGFR and Src restored gefitinib sensitivity in PC9-GR in vitro and in vivo. In conclusion, our results indicate that Src-mediated ERK reactivation may play a role in a novel gefitinib resistance mechanism, and that the combined use of gefitinib with a Src inhibitor may be a potent strategy to overcome this resistance.

DOI： 10.1016/j.yexcr.2014.01.007

Src mediates ERK reactivation in gefitinib resistance in non-small cell lung cancer Reviewed

Ochi Nobuaki, Takigawa Nagio, Harada Daijiro, Yasugi Masayuki, Ichihara Eiki, Hotta Katsuyuki, Tabata Masahiro, Tanimoto Mitsune, Kiura Katsuyuki

Experimental Cell Research 322 ( 1 ) 168 - 177 2014.3

Effect of AZD1480 in an epidermal growth factor receptor-driven lung cancer model. International journal

Toshi Murakami, Nagio Takigawa, Takashi Ninomiya, Nobuaki Ochi, Masaaki Yasugi, Yoshihiro Honda, Toshio Kubo, Eiki Ichihara, Katsuyuki Hotta, Mitsune Tanimoto, Katsuyuki Kiura

Lung cancer (Amsterdam, Netherlands) 83 ( 1 ) 30 - 6 2014.1

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

OBJECTIVE: STAT3 plays a vital role in inducing and maintaining a pro-carcinogenic inflammatory microenvironment and is reported to be a critical mediator of the oncogenic effects of EGFR mutations. STAT3 activation is mediated through JAK family kinases. We investigated the effect of the JAK1/2 inhibitor AZD1480 on lung tumors induced by an activating EGFR mutation. MATERIALS AND METHODS: Three EGFR tyrosine kinase inhibitor-resistant cell lines (RPC-9, PC-9/Van-R and PC-9/ER3) established from PC-9 harboring an EGFR exon19 deletion mutation were used. Growth inhibition was measured using an MTT assay. Effects of AZD1480 were also evaluated in the xenograft model and in the EGFR transgenic mice model. Protein expressions were assessed by immunoblotting and immunohistochemistry. Group differences were compared using Student's t-test. To evaluate the efficacy of AZD1480 on survival, AZD1480 or vehicle was administered orally from 7 weeks of age of the transgenic mice. Overall survival curves were calculated using the Kaplan-Meier method. RESULTS: The sensitivities of resistant and parent cells to AZD1480 were similar in vitro. AZD1480 (30 or 50 mg/kg/day, per os) reduced angiogenesis and revealed significant tumor regression in a mouse xenograft model. Subsequently, the transgenic mice were treated with AZD1480 (30 mg/kg/day) or vehicle alone. The numbers of lung tumors (long axis exceeding 1mm) in the AZD1480-treated group and control group were 0.37±0.18 and 2.25±0.53 (p<0.001), respectively. AZD1480 treatment suppressed pSTAT3, pJAK1, pJAK2 and angiogenesis. The median survival time in the AZD1480-treated group (217 days) was significantly greater than that in the control group (106 days) (log-rank test, p<0.0001). CONCLUSION: AZD1480 may be effective against lung tumors driven by an activating EGFR mutation.

DOI： 10.1016/j.lungcan.2013.10.011

Lower gefitinib dose led to earlier resistance acquisition before emergence of T790M mutation in epidermal growth factor receptor-mutated lung cancer model. International journal

Hiromi Hayakawa, Eiki Ichihara, Kadoaki Ohashi, Takashi Ninomiya, Masayuki Yasugi, Saburo Takata, Katsuya Sakai, Kunio Matsumoto, Nagio Takigawa, Mitsune Tanimoto, Katsuyuki Kiura

Cancer science 104 ( 11 ) 1440 - 6 2013.11

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

Non-small-cell lung cancers with epidermal growth factor receptor (EGFR) mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs); however, unlike cytotoxic agents, it is generally accepted that minimal doses of drugs inhibiting target molecules are sufficient when molecular-targeted agents, including EGFR-TKIs, are used. Thus, any utility of higher doses remains unclear. We compared low-dose (15 mg/kg) gefitinib therapy with high-dose (50 mg/kg) therapy using an EGFR-mutated lung cancer xenograft model. Both gefitinib doses induced tumor shrinkage, but tumors regrew in the low-dose group within 1 month, whereas tumors in the high-dose group did not. Neither the T790M mutation nor MET amplification was apparent in regrown tumors. We also compared outcomes after two doses of gefitinib (5 and 25 mg/kg) in a transgenic EGFR-mutated lung cancer mouse model. In line with the results obtained using the xenograft model, both gefitinib doses completely inhibited tumor growth, but tumors treated with the lower dose of gefitinib developed earlier drug resistance. In conclusion, a low gefitinib dose caused tumors to become drug-resistant prior to acquisition of the T790M mutation or MET amplification in EGFR-mutated models of lung cancer. This suggests that it is important to optimize the EGFR-TKI dose for treatment of EGFR mutation-associated lung cancer. Gefitinib may need to be given at a dose greater than the minimum required for inhibition of target molecules.

DOI： 10.1111/cas.12284

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