研究者詳細 - 豊岡　伸一

論文 - 豊岡　伸一

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Anti-tumor effect of neratinib against lung cancer cells harboring HER2 oncogene alterations. 査読国際誌

Yusuke Ogoshi, Kazuhiko Shien, Takahiro Yoshioka, Hidejiro Torigoe, Hiroki Sato, Masakiyo Sakaguchi, Shuta Tomida, Kei Namba, Eisuke Kurihara, Yuta Takahashi, Ken Suzawa, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

Oncology letters 17 ( 3 ) 2729 - 2736 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Human epidermal growth factor receptor 2 (HER2) is a member of the ErbB family of receptor tyrosine kinases. Numerous studies have reported the amplification and overexpression of HER2 in several types of cancer, including non-small cell lung cancer (NSCLC). However, the benefits of HER2-targeted therapy have not been fully established. In the present study, the anti-tumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), against NSCLC cells harboring HER2 alterations was investigated. The sensitivity of normal bronchial epithelial cells (BEAS-2B) ectopically overexpressing wild-type or mutant HER2 to neratinib was assessed. Furthermore, the anti-tumor activity of neratinib in several NSCLC cell lines harboring HER2 alterations was determined in vitro and in vivo, and the association between their genetic alterations and sensitivity to neratinib treatment was investigated. BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D and S310F) exhibited constitutive autophosphorylation of HER2, as determined by western blotting. While these BEAS-2B cells were sensitive to neratinib, they were insensitive to erlotinib, a first-generation epidermal growth factor receptor-TKI. Neratinib also exerted anti-proliferative effects on HER2-altered (H2170, Calu-3 and H1781) NSCLC cell lines. Neratinib was also demonstrated to exert strong tumor growth inhibitory activity in mouse xenograft models using HER2-altered lung cancer cells. The results of the present study strongly suggest that neratinib has potential as a promising therapeutic option for the treatment of HER2-altered NSCLC.

DOI： 10.3892/ol.2019.9908

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Feasibility of lung transplantation from donors mechanically ventilated for prolonged periods. 査読

Seiichiro Sugimoto, Takeshi Kurosaki, Shinji Otani, Shin Tanaka, Yukiko Hikasa, Masaomi Yamane, Shinichi Toyooka, Motomu Kobayashi, Takahiro Oto

Surgery today 49 ( 3 ) 254 - 260 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: When patients are mechanically ventilated for more than 5 days, they are usually declined as donors for lung transplantation (LTx); thus, the long-term outcomes of LTx from such donors remain unclear. We investigated the feasibility of LTx from donors that had been mechanically ventilated for prolonged periods. METHODS: The subjects of this retrospective comparative investigation were 31 recipients of LTx from donors who had been mechanically ventilated for < 5 days (short-term group) and 50 recipients of LTx from donors who had been mechanically ventilated for ≥ 5 days (long-term group). RESULTS: The median duration of donor mechanical ventilation was 3 days in the short-term group and 8.5 days in the long-term group. However, other than the difference in the duration of donor ventilation, there were no significant differences in the clinical characteristics of the donors or recipients between the groups. The overall survival rate after LTx was comparable between the long-term group and short-term group (5-year survival rate, 66.6% vs. 75.2%). CONCLUSION: The potential inclusion of donors who have been on mechanical ventilation for more than 5 days could be a feasible strategy to alleviate donor organ shortage.

DOI： 10.1007/s00595-018-1730-z

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Lung transplant candidates with idiopathic pulmonary fibrosis and long-term pirfenidone therapy: Treatment feasibility influences waitlist survival. 査読国際誌

Shin Tanaka, Kentaroh Miyoshi, Hisao Higo, Takeshi Kurosaki, Shinji Otani, Seiichiro Sugimoto, Masaomi Yamane, Katsuyuki Kiura, Shinichi Toyooka, Takahiro Oto

Respiratory investigation 57 ( 2 ) 165 - 171 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronically progressive lung disease with exceptionally poor prognosis. While lung transplantation (LTx) is considered the last-resort therapeutic option, dismal waitlist mortality still hampers the salvage of patients with IPF. Pirfenidone, originally designed for IPF treatment, has increasingly been utilized. This study aimed to evaluate whether Pirfenidone could influence outcomes of patients with IPF on the Japanese LTx waitlist. METHODS: This retrospective single-center cohort study included 25 consecutive patients with IPF who were registered as LTx candidates at our institution between July 1999 and August 2016. Patients with a history of pretransplant Pirfenidone therapy (Pirfenidone group) were compared with those with no history (non-Pirfenidone group). RESULTS: In total, 6 (24%) patients received Pirfenidone as pretransplant therapy for 45.2 (range, 18.6-66.8) months. During the treatment period, the Pirfenidone group achieved a significant reduction in the decline rate of the forced vital capacity (-6.2% vs. -0.3%, p = 0.04) and a lower lung allocation score (31 vs. 41, p = 0.013) compared with the non-Pirfenidone group. The Pirfenidone group exhibited 100% waitlist survival three years after registration that was comparable to other indications, and 66% of the patients were still alive at the time of organ availability. No patient in the Pirfenidone group developed Pirfenidone-related surgical complications postoperatively. CONCLUSIONS: Patients with IPF successfully managed with long-term Pirfenidone therapy achieved favorable outcomes after LTx registration, comparable to other patients with LTx indications. The tolerability to antifibrotic therapy can be a predictor of waitlist survival.

DOI： 10.1016/j.resinv.2018.12.002

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A single-nucleotide polymorphism in a gene modulating glucocorticoid sensitivity is associated with the decline in total lung capacity after lung transplantation. 査読

Haruchika Yamamoto, Seiichiro Sugimoto, Shin Tanaka, Takeshi Kurosaki, Shinji Otani, Masaomi Yamane, Naruto Taira, Takahiro Oto, Shinichi Toyooka

Surgery today 49 ( 3 ) 268 - 274 2019年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Glucocorticoids are used to prevent chronic lung allograft dysfunction (CLAD) after lung transplantation (LT). Our study was aimed at assessing the association between the glucocorticoid-induced transcript 1 gene (GLCCI1) variant, which modulates glucocorticoid sensitivity, and the postoperative lung function and development of CLAD after LT. METHODS: A total of 71 recipients of LT were genotyped for the GLCCI1 variant (rs37972) and divided into three groups: the homozygous mutant allele (TT) group, the heterozygous mutant allele (CT) group, and the wild-type allele (CC) group. The results of pulmonary function tests were compared with the postoperative baseline values. RESULTS: The total lung capacity (TLC) in the TT group was significantly lower than that in the CC group at 3 years after LT (P = 0.029). In the recipients of cadaveric LT, the TLC and forced expiratory volume in 1 s in the TT group were significantly lower than those in the CC groups, resulting in a significant worse CLAD-free survival at 3 years after LT (P = 0.016). CONCLUSION: The GLCCI1 variant was associated with a significant decrease of the TLC at 3 years after LT and the development of CLAD at 3 years, especially in patients undergoing cadaveric LT.

DOI： 10.1007/s00595-018-1717-9

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チームアプローチで実現するゲノム医療と薬剤師の役割ゲノム医療におけるデータサイエンティストの役割と育成

冨田秀太, 森田瑞樹, 山下範之, 平沢晃, 豊岡伸一

日本薬学会年会要旨集 139年会 ( 1 ) 264 - 264 2019年3月

肺癌患者に対する化学放射線療法は大動脈石灰化を増悪させる(Chemoradiation Therapy to Patients with Lung Cancer Exacerbates Aortic Calcification)

三木崇史, 三好亨, 市川啓之, 宮内俊策, 宗淳一, 豊岡伸一, 中村一文, 森田宏, 伊藤浩

日本循環器学会学術集会抄録集 83回 OJ33 - 4 2019年3月

Application of amplicon-based targeted sequencing with the molecular barcoding system to detect uncommon minor EGFR mutations in patients with treatment-naïve lung adenocarcinoma. 査読国際誌

Namba K, Tomida S, Matsubara T, Takahashi Y, Kurihara E, Ogoshi Y, Yoshioka T, Takeda T, Torigoe H, Sato H, Shien K, Yamamoto H, Soh J, Tsukuda K, Toyooka S

BMC cancer 19 ( 1 ) 175 - 175 2019年2月

Activation of AXL as a Preclinical Acquired Resistance Mechanism Against Osimertinib Treatment in EGFR-Mutant Non-Small Cell Lung Cancer Cells. 査読国際誌

Kei Namba, Kazuhiko Shien, Yuta Takahashi, Hidejiro Torigoe, Hiroki Sato, Takahiro Yoshioka, Tatsuaki Takeda, Eisuke Kurihara, Yusuke Ogoshi, Hiromasa Yamamoto, Junichi Soh, Shuta Tomida, Shinichi Toyooka

Molecular cancer research : MCR 17 ( 2 ) 499 - 507 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.

DOI： 10.1158/1541-7786.MCR-18-0628

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Demographics, Safety and Quality, and Prognostic Information in Both the Seventh and Eighth Editions of the TNM Classification in 18,973 Surgical Cases of the Japanese Joint Committee of Lung Cancer Registry Database in 2010. 査読国際誌

Okami J, Shintani Y, Okumura M, Ito H, Ohtsuka T, Toyooka S, Mori T, Watanabe SI, Date H, Yokoi K, Asamura H, Nagayasu T, Miyaoka E, Yoshino I, Japanese Join, Committee of Lung, Cancer Registry

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 14 ( 2 ) 212 - 222 2019年2月

NEUROPLASTIN-β MEDIATES S100A8/A9-INDUCED LUNG CANCER DISSEMINATIVE PROGRESSION 査読

Sumardika IW, Chen Y, Tomonobu N, Kinoshita R, Ruma IMW, Sato H, Kondo E, Inoue Y, Yamauchi A, Murata H, Yamamoto KI, Tomida S, Shien K, Yamamoto H, Soh J, Futami J, Putranto EW, Hibino T, Nishibori M, Toyooka S, Sakaguchi M

Molecular Carcinogenesis 2019年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

Compiling evidence indicates an unusual role of extracellular S100A8/A9 in cancer metastasis. S100A8/A9 secreted from either cancer cells or normal cells including epithelial and inflammatory cells stimulates cancer cells through S100A8/A9 sensor receptors in an autocrine or paracrine manner, leading to cancer cell metastatic progression. We previously reported a novel S100A8/A9 receptor, neuroplastin-β (NPTNβ), which plays a critical role in atopic dermatitis when it is highly activated in keratinocytes by an excess amount of extracellular S100A8/A9 in the inflammatory skin lesion. Interestingly, our expression profiling of NPTNβ showed significantly high expression levels in lung cancer cell lines in a consistent manner. We hence aimed to determine the significance of NPTNβ as an S100A8/A9 receptor in lung cancer. Our results showed that NPTNβ has strong ability to induce cancer-related cellular events, including anchorage-independent growth, motility and invasiveness, in lung cancer cells in response to extracellular S100A8/A9, eventually leading to the expression of a cancer disseminative phenotype in lung tissue in vivo. Mechanistic investigation revealed that binding of S100A8/A9 to NPTNβ mediates activation of NFIA and NFIB and following SPDEF transcription factors through orchestrated upstream signals from TRAF2 and RAS, which is linked to anchorage-independent growth, motility and invasiveness. Overall, our results indicate the importance of the S100A8/A9-NPTNβ axis in lung cancer disseminative progression and reveal a pivotal role of its newly identified downstream signaling, TRAF2/RAS-NFIA/NFIB-SPDEF, in linking to the aggressive development of lung cancers. This article is protected by copyright.

DOI： 10.1002/mc.22987

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Detection of lung cancer cells using a terahertz chemical microscope

Kosuke Sato, Masahiro Iida, Hirofumi Inoue, Toshihiko Kiwa, Shinichi Toyooka, Keiji Tsukada

Optics InfoBase Conference Papers Part F146-JSAP 2019 2019年

Long-term spontaneous remission with active surveillance in IgG4-related pleuritis: A case report and literature review. 査読

Makimoto G, Ohashi K, Taniguchi K, Soh J, Taniguchi A, Miyahara N, Toyooka S, Yoshino T, Maeda Y, Kiura K

Respiratory medicine case reports 28 100938 2019年

多発小腸GISTに対し手術を施行した神経線維腫症1型の1例

母里淑子, 藤原俊義, 重安邦俊, 吉岡貴裕, 永坂岳司, 原賀順子, 香川俊輔, 寺石文則, 豊岡伸一, 平沢晃

家族性腫瘍 19 ( 2 ) 77 - 82 2019年

記述言語：日本語出版者・発行元：日本家族性腫瘍学会

症例は54歳男性．大量出血を伴う小腸多発GIST（Gastrointestinal stromal tumor）を認めて緊急入院となった．姉が神経線維腫症1型（neurofibromatosis type 1:NF1）と診断されており，患者にもおよそ20個の神経線維腫を疑う腫瘤とcafé au lait斑を6個以上認めたためNF1と診断した．出血コントロール目的に開腹手術を行ったが，GISTはおよそ20個多発しており，大量小腸切除を避けるために10mm以上の腫瘍のみ外科的切除を行い，多発微小腫瘍は経過観察とした不完全切除を選択した．切除標本の病理検査では紡錘形核と好酸性胞体を有する紡錘形細胞が密に錯綜する腫瘍を認め，免疫染色でKIT陽性．核分裂数は5以下/50HPFsであり低悪性度GISTと診断した．NF1に伴うGISTは比較的予後が良いとの報告もあるが，このような多発微小病変については明らかな治療指針がない．今後さらなる症例の集積と検討を要する．

DOI： 10.18976/jsft.19.2_77

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SPRED2 deficiency may lead to lung ischemia-reperfusion injury via ERK1/2 signaling pathway activation. 査読

Masanori Okada, Masaomi Yamane, Sumiharu Yamamoto, Shinji Otani, Kentaroh Miyoshi, Seiichiro Sugimoto, Akihiro Matsukawa, Shinichi Toyooka, Takahiro Oto, Shinichiro Miyoshi

Surgery today 48 ( 12 ) 1089 - 1095 2018年12月

記述言語：英語掲載種別：研究論文（学術雑誌）

PURPOSE: Inflammatory changes during lung ischemia-reperfusion injury (IRI) are related to the activation of the extracellular signal-regulated kinase (ERK)1/2 signaling pathway. Sprouty-related EVH1 (enabled/vasodilator-stimulated phosphoprotein homology 1)-domain-containing proteins (SPREDs) are known inhibitors of ERK1/2 signaling. The role of SPRED2 in lung IRI was examined in a left hilar clamp mouse model. METHODS: C57BL/6 wild-type (WT) and Spred2-/- mice were used in the left hilar clamp model. Experimental groups underwent 30 min of left hilar clamping followed by 1 h of reperfusion. U0126, an ERK1/2 inhibitor, was administered to Spred2-/- mice with reperfused lungs. RESULTS: The partial pressures of oxygen of the Spred2-/- mice after reperfusion were significantly worse than those of WT mice (p < 0.01). Spred2-/- mice displayed more severe injuries than WT mice with increased neutrophil infiltration observed by a histological evaluation and flow cytometry (p < 0.001). This severe inflammation was inhibited by U0126. In addition, the rate of ERK1 activation was significantly higher in the lungs of Spred2-/- mice after reperfusion than in WT mice according to a Western blot analysis (p < 0.05). CONCLUSION: The activation of the ERK1/2 signaling pathway influences the severity of lung IRI, causing inflammation with neutrophil infiltration. SPRED2 may be a promising target for the suppression of lung IRI.

DOI： 10.1007/s00595-018-1696-x

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Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis. 査読国際誌

Yuta Takahashi, Kazuhiko Shien, Shuta Tomida, Shinsuke Oda, Takehiro Matsubara, Hiroki Sato, Ken Suzawa, Eisuke Kurihara, Yusuke Ogoshi, Kei Namba, Takahiro Yoshioka, Hidejiro Torigoe, Hiromasa Yamamoto, Junichi Soh, Shinichi Toyooka

Cancer science 109 ( 11 ) 3634 - 3642 2018年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer-related oncogenes using next-generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.

DOI： 10.1111/cas.13797

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Study Protocol: Phase-Ib Trial of Nivolumab Combined With Metformin for Refractory/Recurrent Solid Tumors. 査読国際誌

Kubo T, Ninomiya T, Hotta K, Kozuki T, Toyooka S, Okada H, Fujiwara T, Udono H, Kiura K

Clinical lung cancer 19 ( 6 ) e861 - e864 2018年11月

Donor-derived cell-free DNA is associated with acute rejection and decreased oxygenation in primary graft dysfunction after living donor-lobar lung transplantation. 査読国際誌

Shin Tanaka, Seiichiro Sugimoto, Takeshi Kurosaki, Kentaroh Miyoshi, Shinji Otani, Ken Suzawa, Shinsuke Hashida, Masaomi Yamane, Takahiro Oto, Shinichi Toyooka

Scientific reports 8 ( 1 ) 15366 - 15366 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Donor-derived cell-free DNA (dd-cf-DNA) has been shown to be an informative biomarker of rejection after lung transplantation (LT) from deceased donors. However, in living-donor lobar LT, because small grafts from blood relatives are implanted with short ischemic times, the detection of dd-cf-DNA might be challenging. Our study was aimed at examining the role of dd-cf-DNA measurement in the diagnosis of primary graft dysfunction and acute rejection early after living-donor lobar LT. Immediately after LT, marked increase of the plasma dd-cf-DNA levels was noted, with the levels subsequently reaching a plateau with the resolution of primary graft dysfunction. Increased plasma levels of dd-cf-DNA were significantly correlated with decreased oxygenation immediately (p = 0.022) and at 72 hours (p = 0.046) after LT. Significantly higher plasma dd-cf-DNA levels were observed in patients with acute rejection (median, 12.0%) than in those with infection (median, 4.2%) (p = 0.028) or in a stable condition (median, 1.1%) (p = 0.001). Thus, measurement of the plasma levels of dd-cf-DNA might be useful to monitor the severity of primary graft dysfunction, and plasma dd-cf-DNA could be a potential biomarker for the diagnosis of acute rejection after LT.

DOI： 10.1038/s41598-018-33848-3

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Dose-Volume Parameters Predict Radiation Pneumonitis after Surgery with Induction Concurrent Chemoradiotherapy for Non-small Cell Lung Cancer. 査読

Ogata T, Katsui K, Yoshio K, Ihara H, Katayama N, Soh J, Kuroda M, Kiura K, Maeda Y, Toyooka S, Kanazawa S

Acta medica Okayama 72 ( 5 ) 507 - 513 2018年10月

Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions. 査読国際誌

Kato Y, Ninomiya K, Ohashi K, Tomida S, Makimoto G, Watanabe H, Kudo K, Matsumoto S, Umemura S, Goto K, Ichihara E, Ninomiya T, Kubo T, Sato A, Hotta K, Tabata M, Toyooka S, Maeda Y, Kiura K

Cancer science 109 ( 10 ) 3149 - 3158 2018年10月

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR-TKIs in non-small cell lung cancer. 査読国際誌

Hiroki Sato, Hiromasa Yamamoto, Masakiyo Sakaguchi, Kazuhiko Shien, Shuta Tomida, Tadahiko Shien, Hirokuni Ikeda, Minami Hatono, Hidejiro Torigoe, Kei Namba, Takahiro Yoshioka, Eisuke Kurihara, Yusuke Ogoshi, Yuta Takahashi, Junichi Soh, Shinichi Toyooka

Cancer science 109 ( 10 ) 3183 - 3196 2018年10月

記述言語：英語掲載種別：研究論文（学術雑誌）

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non-small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide-3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR-TKI-resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single-agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal-epithelial transition factor amplification, induction of epithelial-to-mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long-term treatment with the combination therapy induced the conversion from EMT to mesenchymal-to-epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR-TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR-TKIs.

DOI： 10.1111/cas.13763

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