Development of metabolic-targeting therapy for overcoming resistance to EGFR-TKIs in non-small cell lung cancer cells

• Project/Area Number: 15K06893
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: Shizuoka Cancer Center Research Institute
• Principal Investigator: Serizawa Masakuni 静岡県立静岡がんセンター(研究所), その他部局等, 主任研究員 (00569915)
• Co-Investigator(Kenkyū-buntansha): 楠原 正俊 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (40169991) ; 高橋 利明 静岡県立静岡がんセンター(研究所), その他部局等, 研究員 (50507415) ; 解良 恭一 群馬大学, 医学部, その他 (40400783)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: がん代謝標的療法 / 肺腺癌 / EGFR-TKI / 耐性 / オシメルチニブ / メタボローム解析

Outline of Final Research Achievements

This study aimed to identify the metabolic profile relevant to EGFR-TKI-resistance and develop targeted therapies for the altered metabolic signature. Especially, we focused on the development of metabolic-targeting therapy for overcoming resistance to the third-generation EGFR-TKI, osimertinib.
We established osimertinib-resistant cell line (EOSR) by using HCC827 lung adenocarcinoma cell line harboring the EGFR-activating mutation. As a result of metabolic profiling with capillary electrophoresis time of-flight mass spectrometry, EOSR cell line showed higher concentration of fructose 1,6-diphosphate and lactic acid compared to HCC827 cells, suggesting metabolic signatures indicative of enhanced glycolysis. Significant gains in the expression of only one gene of the hexokinase family was also detected in EOSR cells. A combination of a competitive glycolytic inhibitor, 2-deoxy-D-glucose, and osimertinib restored osimertinib sensitivity in the EOSR cells showing glycolysis dependence.

Research Products

• [Journal Article] Whole exome sequencing detects variants of genes that mediate response to anticancer drugs (2017)
  • Author(s): Ohnami S, Nagashima T, Urakami K, Shimoda Y, Kamada F, Saito J, Naruoka A, Serizawa M, Masuda Y, Ohnami S, Kusuhara M, Yamaguchi K.
  • Journal Title: The Journal of Toxicological Sciences Volume: 42 Issue: 2 Pages: 137-144
  • DOI: 10.2131/jts.42.137
  • NAID: 130005450526
  • ISSN: 0388-1350, 1880-3989
  • Peer Reviewed / Open Access
• [Journal Article] Integrated analysis of gene expression and copy number identified potential cancer driver genes with amplification-dependent overexpression in 1,454 solid tumors. (2017)
  • Author(s): Ohshima K, Hatakeyama K, Nagashima T, Watanabe Y, Kanto K, Doi Y, Ide T, Shimoda Y, Tanabe T, Ohnami S, Ohnami S, Serizawa M, Maruyama K, Akiyama Y, Urakami K, Kusuhara M, Mochizuki T, Yamaguchi K
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 641-641
  • DOI: 10.1038/s41598-017-00219-3
  • Peer Reviewed / Open Access
• [Journal Article] Comparison of clinically relevant mutation profiles between preoperative biopsy and corresponding surgically resected specimens in Japanese patients with non-small cell lung cancer by amplicon-based massively parallel sequencing. (2017)
  • Author(s): Isaka M
  • Journal Title: Clin Lung Cancer Volume: 18 Issue: 5 Pages: 519-526
  • DOI: 10.1016/j.cllc.2016.11.022
  • Peer Reviewed / Open Access
• [Journal Article] <b>Comprehensive analysis of gene mutation and expression profiles in neuroendocrine carcinomas of the </b><b>stomach </b> (2017)
  • Author(s): Makuuchi R, Terashima M, Kusuhara M, Nakajima T, Serizawa M, Hatakeyama K, Ohshima K, Urakami K, Yamaguchi K.
  • Journal Title: Biomedical Research Volume: 38 Issue: 1 Pages: 19-27
  • DOI: 10.2220/biomedres.38.19
  • NAID: 130005242938
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] <b>Metabolic profiling of gemcitabine- and paclitaxel-treated immortalized human pancreatic cell lines with K-RAS</b>^{<b>G12D </b>} (2017)
  • Author(s): Todaka A, Umehara R, Sasaki K, Serizawa M, Urakami K, Kusuhara M, Yamaguchi K, Yasui H.
  • Journal Title: Biomedical Research Volume: 38 Issue: 1 Pages: 29-40
  • DOI: 10.2220/biomedres.38.29
  • NAID: 130005242936
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] Comprehensive characterization of genes associated with the TP53 signal transduction pathway in various tumors. (2017)
  • Author(s): Ohnami S, Ohshima K, Nagashima T, Urakami K, Shimoda Y, Saito J, Naruoka A, Hatakeyama K, Mochizuki T, Serizawa M, Ohnami S, Kusuhara M, Yamaguchi K
  • Journal Title: Molecular and Cellular Biochemistry Volume: March Issue: 1-2 Pages: 1-11
  • DOI: 10.1007/s11010-017-2977-1
  • Peer Reviewed / Open Access
• [Journal Article] Plasma epidermal growth factor receptor mutation testing with achip-based digital PCR system in patients with advanced non-smallcell lung cancer (2017)
  • Author(s): Kasahara N, Kenmotsu H, Serizawa M, Umehara R, Ono A, Hisamatsu Y, Wakuda K, Omori S, Nakashima K, Taira T, Naito T, Murakami H, Koh Y, Mori K, Endo M, Nakajima T, Yamada M, Kusuhara M, Takahashi T.
  • Journal Title: Lung Cancer Volume: 106 Pages: 138-144
  • DOI: 10.1016/j.lungcan.2017.02.001
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] <b>Next generation sequencing approach for detecting 491 fusion genes from human </b><b>cancer </b> (2016)
  • Author(s): 1.Urakami K, Shimoda Y, Ohshima K, Nagashima T, Serizawa M, Tanabe T, Saito J, Usui T, Watanabe Y, Naruoka A, Ohnami S, Ohnami S, Mochizuki T, Kusuhara M, Yamaguchi K.
  • Journal Title: Biomedical Research Volume: 37 Issue: 1 Pages: 51-62
  • DOI: 10.2220/biomedres.37.51
  • NAID: 130005128377
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] <b>Prevalence of low-penetrant germline </b><i><b>TP53</b></i><b> D49H mutation in Japanese cancer </b><b>patients </b> (2016)
  • Author(s): Yamaguchi Y, Torisu H, Kira R, Ishizaki Y, Sakai Y, Sanefuji M, Ichiyama T, Oka A, Kishi T, Kimura S, Kubota M, Takanashi J, Takahashi Y, Tamai H, Natsume J, Hamano S, Hirabayashi S, Maegaki Y, Mizuguchi M, Minagawa K, Yoshikawa H, Kira J, Kusunoki S, Hara T.
  • Journal Title: Biomedical Research Volume: 37 Issue: 4 Pages: 259-264
  • DOI: 10.2220/biomedres.37.259
  • NAID: 130005405218
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] <b>Optimizing an ion semiconductor sequencing data analysis method to identify somatic mutations in the genomes of cancer cells in clinical tissue </b><b>samples </b> (2016)
  • Author(s): Nagashima T, Shimoda Y, Tanabe T, Naruoka A, Saito J, Serizawa M, Ohshima K, Urakami K, Ohnami S, Ohnami S, Mochizuki T, Kusuhara M, Yamaguchi K
  • Journal Title: Biomedical Research Volume: 37 Issue: 6 Pages: 359-366
  • DOI: 10.2220/biomedres.37.359
  • NAID: 130005252642
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] <b>Integrated next-generation sequencing analysis of whole exome and 409 cancer-related </b><b>genes </b> (2016)
  • Author(s): Shimoda Y, Nagashima T, Urakami K, Tanabe T, Saito J, Naruoka A, Serizawa M, Mochizuki T, Ohshima K, Ohnami S, Ohnami S, Kusuhara M, Yamaguchi K
  • Journal Title: Biomedical Research Volume: 37 Issue: 6 Pages: 367-379
  • DOI: 10.2220/biomedres.37.367
  • NAID: 130005252643
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] Prospective analysis on oncogenic driver mutations and environmental factors: Japan Molecular Epidemiology for lung cancer study (JME) (2016)
  • Author(s): 2.Tomoya Kawaguchi, Yasuhiro Koh, Masahiko Ando, Norimasa Ito, Sadanori Takeo, Hirofumi Adachi, Tsutomu Tagawa, Seiichi Kakegawa, Motohiro Yamashita, Kazuhiko Kataoka, Yukito Ichinose, Yukiyasu Takeuchi, Masakuni Serizawa, Akihiro Tamiya, Shigeki Shimizu, Naoki Yoshimoto, Akihito Kubo, Shun-ichi Isa, Hideo Saka
  • Journal Title: J Clin Oncol Volume: 34 Issue: 19 Pages: 2247-2257
  • DOI: 10.1200/jco.2015.64.2322
  • Peer Reviewed / Open Access
• [Journal Article] Drastic initial response and subsequent response to two ALK inhibitors in a patient with a highly aggressive ALK-rearranged inflammatory myofibroblastic tumor arising in the pleural cavity. (2016)
  • Author(s): Ono A, Murakami H, Serizawa M, Wakuda K, Kenmotsu H, Naito T, Taira T, Koh Y, Ohde Y, Nakajima T, Endo M, Takahashi T
  • Journal Title: Lung Cancer. Volume: 99 Pages: 151-154
  • DOI: 10.1016/j.lungcan.2016.07.002
  • Peer Reviewed / Open Access
• [Journal Article] Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients. (2016)
  • Author(s): Ko R, Kenmotsu H, Serizawa M, Koh Y, Wakuda K, Ono A, Taira T, Naito T, Murakami H, Isaka M, Endo M, Nakajima T, Ohde Y, Yamamoto N, Takahashi K, Takahashi T
  • Journal Title: BMC Cancer. Volume: 16 Pages: 864-864
  • Peer Reviewed / Open Access
• [Journal Article] Novel tumor-specific mutations in receptor tyrosine kinase subdomain IX significantly reduce extracellular signal-regulated kinase activity (2016)
  • Author(s): Masakuni Serizawa, Masatoshi Kusuhara, Sumiko Ohnami, Takeshi Nagashima, Yuji Shimoda, Keiichi Ohshima, Tohru Mochizuki, Kenichi Urakami, Ken Yamaguchi
  • Journal Title: Anticancer Research Volume: -
  • Peer Reviewed
• [Presentation] Development of metabolic-targeting therapy for overcoming resistance to osimertinib in non-small cell lung cancer cells (2018)
  • Author(s): Masakuni Serizawa, Rina Umehara, Keiichi Ohshima, Kenichi Urakami, Takeshi Nagashima, Ken Yamaguchi, Kyoichi Kaira, Toshiaki Takahashi, Masatoshi Kusuhara
  • Organizer: AACR Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] 非小細胞肺癌治療におけるEGFRチロシンキナーゼ阻害剤耐性の克服を目的とする代謝標的治療法の開発 (2017)
  • Author(s): 梅原里奈、楠原正俊 、大島啓一、浦上研一、解良恭一、高橋利明、山口 建 、芹澤昌邦
  • Organizer: 第76回日本癌学会総会
• [Presentation] Systematic phenotyping of novel tumor-specific mutations in receptor tyrosine kinases detected in 1,685 cancer patients (2016)
  • Author(s): 芹澤昌邦 、長嶋剛史 、下田勇治 、大浪俊平 、大浪澄子、大島啓一、望月徹、中島 孝 、浦上研一、楠原正俊 、山口 建
  • Organizer: 第75回日本癌学会総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-10-06