A study of secondary resistance mechanism for molecular target drugs in gastrointestinal stromal tumors

• Project/Area Number: 19590410
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Hyogo College of Medicine
• Principal Investigator: HIROTA Seiichi Hyogo College of Medicine, 医学部, 教授 (50218856)
• Project Period (FY): 2007 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2008: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 腫瘍 / c-kit遺伝子 / 機能獲得性突然変異 / 分子標的治療 / イマチニブ / 二次耐性 / 付加変異 / exon 13 / exon 17 / exon13 / exon17

Research Abstract

We first reported that an imatinib-secondary resistant lesion had secondary c-kit gene mutation in addition to primary c-kit gene mutation. Through analysis of many imatinib-secondary resistant lesions, 70 to 80% of them were proved to have secondary c-kit gene mutations in addition to primary c-kit gene mutations. Most of the secondary c-kit gene mutations were present at exon 13 or exon 17.

Research Products

• [Journal Article] Surgical resection of gastrointestinal stromal tumor of esophagus following preoperative imatinib treatment: a case report (2010)
  • Author(s): S ato H, Kanda T, Hirota S, Bamba T, Sakamoto K, Kosugi S, Matsuki A, Mashima Y, Watanabe G, Hatakeyama K
  • Journal Title: Esophagus 7 Pages: 65-69
  • Peer Reviewed
• [Journal Article] Urgent surgery for intraperitoneal bleeding from GIST during imatinib therapy (2010)
  • Author(s): E nomoto T, Kanda T, Yajima K, Hirota S, Matsuki A, Kosugi S-I, Kato T, Ajioka Y, Hatakeyama K
  • Journal Title: Clin J Gastroenterol 3 Pages: 73-77
  • Peer Reviewed
• [Journal Article] Intracranial metastasis from an esophageal gastrointestinal stromal tumor (2010)
  • Author(s): H amada S, Itami A, Watanabe G, Nakayama S, Tanaka E, Hojo M, Yoshizawa A, Hirota S, Sakai Y
  • Journal Title: Intern Med 49 Pages: 781-785
  • NAID: 130000251867
  • Peer Reviewed
• [Journal Article] Surgical resection of gastrointestinal stromal tumor of esophagus following preoperative imatinib treatment : a case report. (2010)
  • Author(s): Sato H
  • Journal Title: Esophagus 7 Pages: 65-69
  • Peer Reviewed
• [Journal Article] Establishment of a lymph node metastasis model from subcutaneous tumors of gastrointestinal stromal tumor model cells (2009)
  • Author(s): S akurama K, Naomoto Y, Ohara T, Watanabe N, Takaoka M, Nagatsuka H, Tomono Y, Tanida T, Noma K, Tanabe S, Fujiwara Y, Motoki T, Shirakawa Y, Yamatsuji T, Hirota S, Taguchi T, Tanaka N
  • Journal Title: Oncol Rep 21 Pages: 407-411
  • Peer Reviewed
• [Journal Article] Inhibition of focal adhesion kinase as a potential therapeutic strategy for Imatinib-resistant gastrointestinal stromal tumor (2009)
  • Author(s): S akurama K, Noma K, Takaoka M, Tomono Y, Watanabe N, Hatakeyama S, Ohmori O, Hirota S, Motoki T, Shirakawa Y, Yamatsuji T, Haisa M, Matsuoka J, Tanaka N, Naomoto Y
  • Journal Title: Mol Cancer Ther 8 Pages: 127-134
  • Peer Reviewed
• [Journal Article] Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene (2009)
  • Author(s): N ishida T, Takahashi T, Nishitani A, Doi T, Shirao K, Komatsu Y, Nakajima K, Hirota S
  • Journal Title: Japanese Study Group on GIST. Int J Clin Oncol 14 Pages: 143-149
  • NAID: 10025147879
  • Peer Reviewed
• [Journal Article] Gastric leiomyosarcoma manifesting peculiar findings: radiological-pathological correlation (2009)
  • Author(s): M asuzawa N, Kishimoto M, Nishimura A, Ichiba N, Aoki E, Yanagibashi K, Hirota S, Yanagisawa A
  • Journal Title: Pathol Int 59 Pages: 306-311
  • NAID: 10027380056
  • Peer Reviewed
• [Journal Article] Involvement of focal adhesion kinase in the progression and prognosis of gastrointestinal stromal tumors (2009)
  • Author(s): K amo N, Naomoto Y, Shirakawa Y, Yamatsuji T, Hirota S, Fujiwaraa Y, Noma K, Sakurama K, Takaoka M, Nagatsuka H, Gunduz M, Matsuoka J, Tanaka N
  • Journal Title: Human Pathol 40 Pages: 1643-1649
  • Peer Reviewed
• [Journal Article] In vivo effect of imatinib on progression of cecal GIST-like tumors in exon 17-type c-kit knock-in mice (2009)
  • Author(s): I shikawa T, Nakai N, Liu N-N, Shiba K, Isozaki K, Matsuda I, Ito K, Fujimoto J, Hatakeyama K, Kanda T, Hirota S
  • Journal Title: Lab Invest 89 Pages: 1161-1168
  • Peer Reviewed
• [Journal Article] Establishment of a lymph node metastasis model from subcutaneous tumors of gastrointestinal stromal tumor model cells. (2009)
  • Author(s): Sakurama K
  • Journal Title: Mol Cancer Ther 8 Pages: 127-134
  • Peer Reviewed
• [Journal Article] Inhibition of focal adhesion kinase as a potential therapeutic strategy for Imatinib-resistant gastrointestinal stromal tumor. (2009)
  • Author(s): Sakurama K
  • Journal Title: Mol Cancer Ther 8 Pages: 127-134
  • Peer Reviewed
• [Journal Article] Sunitinib-resistant gastrointestinal stromal tumors harbor cis-mutations in the activation loop of the KIT gene. (2009)
  • Author(s): Nishida T
  • Journal Title: Int J Clin Oncol 14 Pages: 143-149
  • Peer Reviewed
• [Journal Article] Gastric leiomyosarcoma manifesting peculiar findings : radiological-pathological correlation. (2009)
  • Author(s): Masuzawa N
  • Journal Title: Pathol Int 59 Pages: 306-301
  • Peer Reviewed
• [Journal Article] Involvement of focal adhesion kinase in the progression and prognosis of gastrointestinal stromal tumors. (2009)
  • Author(s): Kamo N
  • Journal Title: Human Pathol 40 Pages: 1643-1649
  • Peer Reviewed
• [Journal Article] In vivo effect of imatinib on progression of cecal GIST-like tumors in exon 17-type c-kit knock-in mice. (2009)
  • Author(s): Ishikawa T
  • Journal Title: Lab Invest 89 Pages: 1161-1168
  • Peer Reviewed
• [Journal Article] Establishment of a lymph node metastasis model from subcutaneous tumors of gastrointestinal stromal tumor model cells. (2009)
  • Author(s): Sakurama K
  • Journal Title: Oncol Rep 21 Pages: 407-411
  • Peer Reviewed
• [Journal Article] Efficacy and Safety Profile of Imatinib Mesylate (STI571) in Japanese Patients with Advanced Gastrointestinal Stromal Tumors: a Phase II Study (STI571B1202) (2008)
  • Author(s): N ishida T, Shirao K, Sawaki A, Koseki M, Okamura T, Ohtsu A, Sugiyama T, Miyakawa K, Hirota S
  • Journal Title: Int J Clin Oncol 13 Pages: 244-251
  • NAID: 10024142467
  • Peer Reviewed
• [Journal Article] Abberant expression of glycosylation in juvenile gastrointestinal stromal tumors (2008)
  • Author(s): T akahashi T, Naka T, Fujimoto M, Serada S, Horino J, Terabe F, Hirota S, Miyoshi E, Hirai T, Nakajima K, Nishitani A, Souma Y, Sawa Y, Nishida T
  • Journal Title: Proteomics Clin Appl 2 Pages: 1246-1254
  • Peer Reviewed
• [Journal Article] Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor (2008)
  • Author(s): N ishida T, Kanda T, Nishitani A, Takahashi T, Nakajima K, Ishikawa T, Hirota S
  • Journal Title: Cancer Sci 99 Pages: 799-804
  • NAID: 10024005223
  • Peer Reviewed
• [Journal Article] Cell adhesion molecule 1 is a novel pancreatic-islet cell adhesion molecule that mediates nerve-islet cell interactions (2008)
  • Author(s): Koma Y, Furuno T, Hagiyama M, Hamaguchi K, Nakanishi M, Masuda M, Hirota S, Yokozaki H, Ito A
  • Journal Title: Gastroenterology 134 Pages: 1544-1554
  • Peer Reviewed
• [Journal Article] Efficacy and safety profile of imatinib mesylate (STI571) in Japanese patients with advanced gastrointestinal stromal tumors : a phase II study (STI571B1202). (2008)
  • Author(s): Nishida T
  • Journal Title: Int J Clin Oncol 13 Pages: 244-251
  • Peer Reviewed
• [Journal Article] Abberant expression of glycosylation in juvenile gastrointestinal stromal tumors. (2008)
  • Author(s): Takahashi T
  • Journal Title: Proteomics Clin Appl 2 Pages: 1246-1254
  • Peer Reviewed
• [Journal Article] Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal stromal tumor. (2008)
  • Author(s): Nishida T
  • Journal Title: Cancer Sci 99 Pages: 799-804
  • Peer Reviewed
• [Journal Article] Cell adhesion molecule 1 is a novel pancreatic-islet cell adhesion molecule that mediates nerve-islet cell interactions. (2008)
  • Author(s): Koma Y
  • Journal Title: Gastroenterology 134 Pages: 1544-1554
  • Peer Reviewed
• [Journal Article] Clinical practice guidelines for gastrointestinal stromal tumor (GIST) in Japan : English version. (2008)
  • Author(s): Nishida T
  • Journal Title: Int J Clin Oncol 13 Pages: 416-430
  • Peer Reviewed
• [Journal Article] Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation (2007)
  • Author(s): N akagomi N, Hirota S
  • Journal Title: Lab Invest 87 Pages: 365-371
  • Peer Reviewed
• [Journal Article] Two cases of gastrointestinal stromal tumor of the stomach with lymph node metastasis (2007)
  • Author(s): S ato T, Kanda T, Nishikura K, Hirota S, Hashimoto K, Nakagawa S, Ohashi M, Hatakeyama K
  • Journal Title: Hapato-Gastroenterol 54 Pages: 1057-1060
  • Peer Reviewed
• [Journal Article] Characterization of tyrosine kinase I domain c-kit gene mutation Asn655Lys newly found in primary jejunal gastrointestinal stromal tumor (2007)
  • Author(s): K inoshita K, Hirota S, Isozaki K, Nishitani A, Tsutsui S, Watabe K, Tamura S, Ishikawa T, Kanda T, Nishida T, Hayashi N
  • Journal Title: Am J Gastroenterol 102 Pages: 1134-1136
  • Peer Reviewed
• [Journal Article] Familial adenomatous polyposis complicated by chronic myelogenous leukemia: response to imatinib mesylate (2007)
  • Author(s): I tsukuma T, Ishikawa H, Misawa M, Kai S, Fujimori Y, Nakagawa K, Hirota S, Sugihara A, Terada N, Hara H
  • Journal Title: J Gastroenterol 42 Pages: 402-405
  • NAID: 10019483270
  • Peer Reviewed
• [Journal Article] Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy (2007)
  • Author(s): Hasegawa J, Kanda T, Hirota S, Fukuda M, Nishitani A, Takahashi T, Kurosaki I, Tsutsui S, Hatakeyama K, Nishida T
  • Journal Title: Int J Clin Oncol 12 Pages: 212-217
  • Peer Reviewed
• [Journal Article] An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors (2007)
  • Author(s): Takahashi T, Nakajima K, Nishitani A, Souma Y, Hirota S, Sawa Y, Nishida T
  • Journal Title: Int J Clin Oncol 12 Pages: 369-374
  • NAID: 10019800300
  • Peer Reviewed
• [Journal Article] A mouse model of human multiple GIST family with KIT-Asp820Tyr mutation generated by knock-in strategy (2007)
  • Author(s): N akai N, Ishikawa T, Nishitani A, Liu N-N, Shincho M, Hao H, Isozaki K, Kanda T, Nishida T, Fujimoto J, Hirota S
  • Journal Title: J Pathol 214 Pages: 302-311
  • Peer Reviewed
• [Journal Article] A mouse model of human multiple GIST family with KIT-Asp820Tyr mutation generated by knock-in strategy (2007)
  • Author(s): Nakai N
  • Journal Title: J Pathol 214 Pages: 302-311
  • Peer Reviewed
• [Journal Article] Surgical interventions for focal progression of advanced gastrointestinal stromal tumors during imatinib therapy (2007)
  • Author(s): Hasegawa J
  • Journal Title: Int J CIin Oncol 12 Pages: 212-217
  • Peer Reviewed
• [Journal Article] An enhanced risk-group stratification system for more practical prognostication of clinically malignant gastrointestinal stromal tumors (2007)
  • Author(s): Takahashi T
  • Journal Title: Int J Clin Oncol 12 Pages: 369-374
  • Peer Reviewed
• [Journal Article] Characterization of tyrosine kinase I domain c-kit gene mutation Asn655Lys newly found in primary jejunal gastrointestinal stromal tumor (2007)
  • Author(s): Kinoshita K
  • Journal Title: Am J Gastroenterol 102 Pages: 1134-1136
  • Peer Reviewed
• [Journal Article] Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation (2007)
  • Author(s): Nakagomi N
  • Journal Title: Lab Invest 87 Pages: 365-371
  • Peer Reviewed
• [Journal Article] Two cases of gastrointestinal stromal tumor of the stomach with lymph node metastasis (2007)
  • Author(s): Sato T
  • Journal Title: Hapato-Gastroenterol 54 Pages: 1057-1060
  • Peer Reviewed
• [Journal Article] Familial adenomatous polyposis complicated by chronic myelo genous leukemia:response to imatinib mesylate (2007)
  • Author(s): Itsukuma T
  • Journal Title: J Gastroenterol 42 Pages: 402-405
  • Peer Reviewed
• [Journal Article] Pleomorphic phenotypes of gastrointestinal stromal tumors at metastatic sites with or without imatinib treatment
  • Author(s): S akamoto K, Sakurai S, Kanda T, Sakuma Y, Hishima T, Hironaka M, Bamba T, Keira Y, Takano Y, Niki T, Hasegawa T, Hirota S
  • Journal Title: Cancer Sci (In press)
  • NAID: 10026592688
  • Peer Reviewed
• [Journal Article] Secondary mutations in the kinase domain of the KIT gene are predominant in imatinib-resistant gastrointestinal Stromal tumor
  • Author(s): Nishida T
  • Journal Title: Cancer Sci (In press)
  • Peer Reviewed
• [Journal Article] Efficacy and Safety Profile of Imatinib Mesylate(STI571)in Japanese Patients with Advanced Gastrointestinal Stromal Tumors: a Phase II Study(STI571B1202)
  • Author(s): Nishida T
  • Journal Title: Int J Clin Oncol (In press)
  • Peer Reviewed
• [Journal Article] Diagnostic efficacy of free to total ratio of prostate-specific antigen and prostate-specific antigen velocity,singly and in combination,in detecting prostate cancer in patients with total serum prostate-specific antigen between 4 and 10ng/ml
  • Author(s): Yamamoto S
  • Journal Title: Int Urol Nephrol (In press)
  • Peer Reviewed
• [Journal Article] Expression of cyclooxygenase-2 and DNA topoisomerase II alpha in precancerous and cancerous lesions of the oral mucosa
  • Author(s): Segawa E
  • Journal Title: Oral Oncol (In press)
  • Peer Reviewed
• [Presentation] mouse model of human GIST (2008)
  • Author(s): Hirota S
  • Organizer: 2008 Korean GIST Multidisciplinary Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2008-11-29
• [Presentation] A mouse model of human GIST. (2008)
  • Author(s): Hirota S
  • Organizer: 2008 Korean GIST Multidisciplinary Symposium
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2008-11-29
• [Presentation] A mouse model of human multiple GIST family with KIT-Asp820Tyr mutation generated by knock-in strategy (2008)
  • Author(s): N akai N, Hirota S, et al
  • Organizer: DDW
  • Place of Presentation: San Diego, USA
  • Year and Date: 2008-05-19
• [Presentation] A mouse model of human multiple GIST family with KIT-Asp820Tyr mutation generated by knock-in strategy. (2008)
  • Author(s): Nakai N
  • Organizer: DDW
  • Place of Presentation: San Diego, USA
  • Year and Date: 2008-05-19
• [Presentation] KIT-Asp820Tyr変異を持つ家族性多発性GTST家系のモデルマウスの作成 (2008)
  • Author(s): 伊藤敬
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-16
• [Presentation] KIT-Asp820Tyr変異を持つ家族性多発性GIST家系のモデルマウスの作成 (2008)
  • Author(s): 伊藤敬, 中井紀博, 新長真由美, 松田育雄, 塚本吉胤, 羽尾裕之, 廣田誠一
  • Organizer: 第97回日本病理学会総会
  • Place of Presentation: 金沢
  • Year and Date: 2008-05-15