Novel biomarkers for EGFR inhibitors in gastroenterological cancers based on CGH analyses

• Project/Area Number: 15H06754
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: National Cancer Center Japan (2016); Kinki University (2015)
• Principal Investigator: Togashi Yosuke 国立研究開発法人国立がん研究センター, 先端医療開発センター, 研究員 (80758326)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: EGFR阻害剤 / 大腸癌 / 膵癌 / FGFRシグナル / PI3Kシグナル / FGF9 / AKT2 / MAP3K10

Outline of Final Research Achievements

The CGH analysis has shown that FGF9, MAP3K10, and AKT2 genes can be related to the resistance to EGFR inhibitors. Using overexpressing cell lines, the resistance has been demonstrated in FGF9 and AKT2 genes, which can be cancelled by FGFR and PI3K inhibitors, respectively, but not in MAP3K10 gene.
In clinical samples, FGF9 amplification 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. In addition, the difference was not significant, pancreatic cancer patients with high levels of Akt2 expression tended to have a poorer response and a shorter progression-free survival period after treatment with an EGFR inhibitor than those with low expression levels.

Research Products

• [Journal Article] Efficacy of irreversible EGFR-TKIs for the uncommon secondary resistant EGFR mutations L747S, D761Y, and T854A. (2017)
  • Author(s): Chiba M, Togashi Y, Bannno E, Kobayashi Y, Nakamura Y, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Mitsudomi T, Nishio K.
  • Journal Title: BMC Cancer. Volume: 17 Issue: 1 Pages: 281-281
  • DOI: 10.1186/s12885-017-3263-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MEK inhibitors against MET-amplified non-small cell lung cancer. (2016)
  • Author(s): Chiba M, Togashi Y, Tomida S, Mizuuchi H, Nakamura Y, Banno E, Hayashi H, Terashima M, De Velasco MA, Sakai K, Fujita Y, Mitsudomi T, Nishio K.
  • Journal Title: Int J Oncol. Volume: 49 Issue: 6 Pages: 2236-2244
  • DOI: 10.3892/ijo.2016.3736
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sensitivities to various EGFR-TKIs of uncommon EGFR mutations L861Q and S768I: what is the optimal EGFR-TKI? (2016)
  • Author(s): Banno E, Togashi Y, Nakamura Y, Chiba M, Kobayashi Y, Hayashi H, Terashima M, de Velasco MA, Sakai K, Fujita Y, Mitsudomi T, Nishio K.
  • Journal Title: Cancer Science Volume: 107 Issue: 8 Pages: 1134-1140
  • DOI: 10.1111/cas.12980
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Afatinib against Esophageal or Head-and-Neck Squamous Cell Carcinoma: Significance of Activating Oncogenic HER4 Mutations in HNSCC. (2016)
  • Author(s): Nakamura Y, Togashi Y, Nakahara H, Tomida S, Banno E, Terashima M, Hayashi H, de Velasco MA, Sakai K, Fujita Y, Okegawa T, Nutahara K, Hamada S, Nishio K.
  • Journal Title: Mol Cancer Ther. Volume: 15 Issue: 8 Pages: 1988-1997
  • DOI: 10.1158/1535-7163.mct-15-0737
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 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 (2016)
  • Author(s): Mizukami T, Togashi Y, Naruki S, Banno E, Terashima M, De Velasco MA, Sakai K, Yoneshige A, Hayashi H, Fujita Y, Tomida S, Nakajima TE, Fujino T, Boku N, Ito A, Nakagawa K, Nishio K.
  • Journal Title: Molecular Carcinogenesis Volume: Epub Issue: 1 Pages: 106-117
  • DOI: 10.1002/mc.22476
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Functional analyses of mutations in receptor tyrosine kinase genes in non-small cell lung cancer: double-edged sword of DDR2 (2016)
  • Author(s): Terashima M, Togashi Y, Sato K, Mizuuchi H, Sakai K, Suda K, Nakamura Y, Banno E, Hayashi H, De Velasco MA, Fujita Y, Tomida S, Mitsudomi T, Nishio K.
  • Journal Title: Clinical Cancer Research Volume: 22 Issue: 14 Pages: 3663-3671
  • DOI: 10.1158/1078-0432.ccr-15-2093
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 稀な EGFR 遺伝子の耐性二次変異（L747S，D761 Y，T854A）における各種 EGFRTKI の感受性 (2016)
  • Author(s): 千葉真人、冨樫庸介、西尾和人、光冨徹哉
  • Organizer: 第57回日本肺癌学会
  • Place of Presentation: 福岡
  • Year and Date: 2016-12-19
• [Presentation] DDR2 E655K mutations proteins are targeted for degradation by the ubiquitin-proteasome pathway and lose their functions (2016)
  • Author(s): Masato Terashima, Yosuke Togashi, Kazuko Sakai, Yu Nakamura, Eri Banno, Marco A.DeVelasco, Yoshihiko Fujita, and Kazuto Nishio
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Afatinib against HNSCC or ESCC: significance of activating oncogenic HER4 mutations in HNSCC (2016)
  • Author(s): Yu Nakamura, Yosuke Togashi, Masato Terashima, Marco A DeVelasco, Kazuko Sakai, Yoshihiko Fujita, Takatsugu Okegawa, Suguru Hamada, Kazuto Nishio
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Anticancer activities of various EGFR-TKIs against uncommon EGFR-mutated non-small cell lung cancer (2016)
  • Author(s): Yosuke Togashi, Masato Chiba, Eri Bannno, Yoshihisa Kobayashi, Hidetoshi Hayashi, Tetsuya Mitsudomi, and Kazuto Nishio
  • Organizer: 第14回日本臨床腫瘍学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2016-07-28
• [Presentation] Clinicopathological and genetic differences between low-grade and high-grade colorectal mucinous adenocarcinoma (2016)
  • Author(s): Yosuke Togashi, Yasumasa Yoshioka, Takaaki Chikugo, Akihiro Kogita, Masataka Taguri, Masato Terashima, Kazuko Sakai, Tadao Tokoro, Kiyotaka Okuno, Kazuto Nishio
  • Organizer: 第14回日本臨床腫瘍学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2016-07-28
• [Presentation] Receptor tyrosine kinase mutations in non-small cell lung cancer (2015)
  • Author(s): Hidetoshi Hayashi, Yosuke Togashi, Masato Terashima, Kazuko Sakai, Hiroshi Mizuuchi, Yoshihisa Kobayashi, Kenichi Suda, Kazuhiko Nakagawa, Tetsuya Mitsudomi, Kazuto Nishio
  • Organizer: European Cancer Congress 2015
  • Place of Presentation: オーストリア・ウィーン
  • Year and Date: 2015-09-25
  • Int'l Joint Research
• [Presentation] FGF9 gene amplification can induce resistance to anti-EGFR therapy in colorectal cancer. (2015)
  • Author(s): Takuro Mizukami, Yosuke Togashi, Eri Banno, Masato Terashima, Marco A de velasco, Kazuko Sakai, Hidetoshi Hayashi, Yoshihiko Fujita, Shuta Tomida, Takako Eguchi Nakajima, Narikazu Boku, Akihiko Ito, Kazuhiko Nakagawa, Kazuto Nishio
  • Organizer: European Cancer Congress 2015
  • Place of Presentation: オーストリア・ウィーン
  • Year and Date: 2015-09-25
  • Int'l Joint Research