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

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15H06754
• Research Institution: National Cancer Center Japan
• Principal Investigator: 冨樫 庸介 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
• Keywords: EGFR阻害剤 / FGF9 / AKT2 / MAP3K10 / 大腸癌 / 膵癌

Outline of Annual Research Achievements

臨床検体のCGH法解析から明らかになったFGF9・MAP3K10・AKT2遺伝子について、それぞれ耐性化への関与を調べたところ、FGF9とAKT2については強制発現株でEGFR阻害剤への耐性化への関与が疑われ、それぞれFGFR阻害剤とPI3K阻害剤で耐性化が解除された。MAP3K10については耐性化は認められなかった。
FGF9については顕著な差が認められたため、nude mouseを用いてin vivoでも検証したところ、in vivoでも同様の耐性ならびにFGFR阻害剤併用の有効性が認められた。さらにFGFRシグナルは血管新生への関与も報告されているが、FGF9強制発現株では血管新生についても増強が認められ、FGFR阻害剤による血管新生の抑制も確認できた。
AKT2の関与について22例の進行膵癌の針生検検体で免疫染色を行ったところ、高発現の患者のほうがerlotinibの効果が悪く、PFSもOSも短い傾向にあった。
以上よりEGFR阻害剤の耐性について大腸癌・膵癌でFGFRシグナルとPI3Kシグナルの関与、ならびにそれぞれの阻害剤併用による有用性が示唆された。

Research Progress Status

28年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

28年度が最終年度であるため、記入しない。

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 Pages: 281
  • DOI: 10.1186/s12885-017-3263-z
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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 (2017)
  • 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: 56 Pages: 106-117
  • DOI: 10.1002/mc.22476.
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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: International Journal of Oncology Volume: 49 Pages: 2236-2244
  • DOI: 10.3892/ijo.2016.3736
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [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 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 S, Okegawa T, Nutahara K, Hamada S, Nishio K.
  • Journal Title: Molecular Cancer Therapeutics Volume: 15 Pages: 1988-1997
  • DOI: 10.1158/1535-7163.MCT-15-0737.
  • Peer Reviewed / 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 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 – 2016-12-21
• [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 – 2016-10-08
• [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 – 2016-10-08
• [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 – 2016-07-30
• [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 – 2016-07-30