EGFR mutant lung cancer and second generation tyrosine kinase inhibitor: acquired resistance and personalized medicine

• Project/Area Number: 16K19989
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory surgery
• Research Institution: Kindai University
• Principal Investigator: KOBAYASHI Yoshihisa 近畿大学, 医学部附属病院, 助教 (30734628)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺癌 / EGFR / チロシンキナーゼ阻害剤 / アファチニブ / ダコミチニブ / L792F / 薬剤耐性 / 分子標的治療 / 耐性機序

Outline of Final Research Achievements

Targeted therapy with tyrosine kinase inhibitors (TKIs) is a standard treatment for patients with epidermal growth factor receptor (EGFR) mutant lung cancer. However, not all EGFR mutations are sensitive to conventional EGFR-TKIs. Additionally, lung cancers inevitably acquire resistance to these TKIs despite the marked initial response.
We found that lung cancers harboring exon 18 mutations were not sensitive to conventional first generation EGFR-TKIs but are sensitive to second generation TKI afatinib. Next, a novel EGFR L792F secondary mutation, in addition to T790M and C797S, was discovered in afatinib-resistant cells. L792F appeared to exhibit sensitivity to other second generation TKI dacomitinib. Dacomitinib induced T790M or C797S secondary mutations as mechanisms of acquired resistance and these mutations were sensitive to currently available TKIs.

Research Products

• [Journal Article] EGFR T790M and C797S Mutations as Mechanisms of Acquired Resistance to Dacomitinib (2018)
  • Author(s): Kobayashi Y, Fujino T, Nishino M, Koga T, Chiba M, Sesumi Y, Ohara S, Shimoji M, Tomizawa K, Takemoto T, Mitsudomi T
  • Journal Title: Journal of Thoracic Oncology Volume: ePub中 Issue: 5 Pages: 727-731
  • DOI: 10.1016/j.jtho.2018.01.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ALK遺伝子転座陽性例への薬物療法-治療開始からラストラインまで (2017)
  • Author(s): 小林祥久、光冨徹哉
  • Journal Title: 臨床腫瘍プラクティス Volume: 13 Pages: 16-20
• [Journal Article] Characterization of EGFR T790M, L792F, and C797S Mutations as Mechanisms of Acquired Resistance to Afatinib in Lung Cancer (2017)
  • Author(s): Kobayashi, Y. Azuma, K. Nagai, H. Kim, Y. H. Togashi, Y. Sesumi, Y. Chiba, M. Shimoji, M. Sato, K. Tomizawa, K. Takemoto, T. Nishio, K. Mitsudomi, T.
  • Journal Title: Molecular Cancer Therapeutics Volume: 16 Pages: 357-364
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Not all epidermal growth factor receptor mutations in lung cancer are created equal: Perspectives for individualized treatment strategy (2016)
  • Author(s): Kobayashi, Y. Mitsudomi, T.
  • Journal Title: Cancer Science Volume: 107 Issue: 9 Pages: 1179-1186
  • DOI: 10.1111/cas.12996
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Mechanisms of acquired resistance to dacomitinib in cell models (2017)
  • Author(s): Kobayashi Y, Fujino T, Nishino M, Ohara S, Sesumi Y, Chiba M, Shimoji M, Tomizawa K, Takemoto T, Mitsudomi T
  • Organizer: World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] Molecular targeted therapy for EGFR mutant lung cancer: mutation-specific drug selection. (2017)
  • Author(s): Kobayashi Y
  • Organizer: The Satelite Symposium of Biological Session of Japan Nucleic Acid Therapeutics
  • Int'l Joint Research / Invited
• [Presentation] アファチニブ獲得耐性機序としてのEGFR二次変異T790M、L792F、C797Sの特徴 (2016)
  • Author(s): 小林祥久、東公一、永井宏樹、金永学、冨樫庸介、瀬角裕一、西野将矢、西平守道、佐藤克明、千葉眞人、下治正樹、富沢健二、武本智樹、西尾和人、光冨徹哉
  • Organizer: 第57回日本肺癌学会学術集会
  • Place of Presentation: 福岡国際会議場 (福岡市)
  • Year and Date: 2016-12-20
• [Presentation] EGFR T790M, L792F, and C797S mutations as mechanisms of acquired resistance to afatinib (2016)
  • Author(s): Kobayashi, Y. Azuma, K. Nagai, H. Kim, Y. H. Togashi, Y. Sesumi, Y. Chiba, M. Shimoji, M. Sato, K. Tomizawa, K. Takemoto, T. Nishio, K. Mitsudomi, T.
  • Organizer: 17th World Conference on Lung Cancer
  • Place of Presentation: ウィーン (オーストリア)
  • Year and Date: 2016-12-07
  • Int'l Joint Research
• [Book] 肺癌診療Q&A 第3版 一つ上を行く診療の実践 (分担執筆 P42-46, P326-329) (2017)
  • Author(s): 小林祥久、光冨徹哉
  • Total Pages: 521
  • Publisher: 中外医学社
  • ISBN: 9784498131002