Mechanistic role of KRAS amplification in gastroesophageal adenocarcinoma

• Project/Area Number: 16H06259
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: Imamura Yu 公益財団法人がん研究会, 有明病院 消化器外科, 副医長 (70583045)
• Research Collaborator: Bass Adam J. Dana-Faber Cancer Insitute ; Haraguchi Ikumi 公益財団法人がん研究会・がん研究所, がんゲノム研究部
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000); Fiscal Year 2018: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000); Fiscal Year 2017: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2016: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
• Keywords: KRAS / 遺伝子増幅 / 食道胃接合部腺癌 / 胃癌 / 食道腺癌 / 食道癌 / 予後 / 分子標的治療 / MEK阻害剤 / copy number variant / 悪性度

Outline of Final Research Achievements

KRAS amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.

Academic Significance and Societal Importance of the Research Achievements

これまでKRAS遺伝子増幅は上部消化器腺癌や卵巣癌で頻度が高いが、その意義は不明である。我々は今回野生型KRAS遺伝子増幅に注目した。このKRAS遺伝子増幅を来した細胞ではKRASタンパクの過剰発現を来たし、MEK阻害剤に抵抗性を示すことが判明した。グアニン交換因子であるSOS1, SOS2, SHP2阻害することでこの抵抗性の状態から脱することを明らかにした。KRAS遺伝子増幅を来す腫瘍においてはMEK阻害剤とSHP2阻害剤の併用が期待できる。KRAS遺伝子に関して変異だけでなく野生株遺伝子増幅の腫瘍悪性化メカニズムを初めて明らかにすることができ、新たな治療体系の確立が可能となる。

Research Products

• [Int'l Joint Research] Dana-Farber Cancer Institute(米国)
• [Int'l Joint Research] Dana-Farber Cancer Institute(米国)
• [Journal Article] Recent incidence trend of surgically resected esophagogastric junction adenocarcinoma and microsatellite instability status in Japanese patients. (2018)
  • Author(s): Imamura Y, Watanabe M, Toihata T, Takamatsu M, Kawachi H, Haraguchi I, Ogata Y, Yoshida N, Saeki H, Oki E, Taguchi K, Yamamoto M, Morita M, Mine S, Hiki N, Baba H, Sano T.
  • Journal Title: Digestion. Volume: 99 Issue: 1 Pages: 6-13
  • DOI: 10.1159/000494406
  • Peer Reviewed / Open Access
• [Journal Article] Targeting wild-type KRAS-amplified gastroesophageal cancer through combined MEK and SHP2 inhibition (2018)
  • Author(s): Wong GS, Watanabe M(34番目), Imamura Y(36番目), Bass AJ (34人省略)
  • Journal Title: Nature Medicine Volume: 24 Issue: 7 Pages: 968-977
  • DOI: 10.1038/s41591-018-0022-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Amplification of Wild-type KRAS Imparts Resistance to Crizotinib in MET Exon 14 Mutant Non?Small Cell Lung Cancer (2018)
  • Author(s): Bahcall M, Awad MM, Sholl LM, Wilson FH, Xu M, Wang S, Palakurthi S, Choi J, Ivanova E, Leonardi GC, Ulrich BC, Paweletz CP, Kirschmeier PT, Watanabe M, Baba H, Nishino M, Nagy RJ, Lanman RB, Capelletti M, Chambers ES, Redig AJ, VanderLaan PA, Costa DB, Imamura Y, Janne PA
  • Journal Title: Clinical Cancer Research Volume: 24 Issue: 23 Pages: 5963-5976
  • DOI: 10.1158/1078-0432.ccr-18-0876
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Preoperative controlling nutritional status (CONUT) is useful to estimate the prognosis after esophagectomy for esophageal cancer. (2017)
  • Author(s): Yoshida N, Harada K, Baba Y, Kosumi K, Iwatsuki M, Kinoshita K, Nakamura K, Sakamoto Y, Miyamoto Y, Karashima R, Mima K, Sawayama H, Ohuchi M, Chikamoto A, Imamura Y, Watanabe M, Baba H.
  • Journal Title: Langenbecks Arch Surg. Volume: 402 Pages: 333-341
  • Peer Reviewed
• [Journal Article] Autophagy Inhibition Dysregulates TBK1 Signaling and Promotes Pancreatic Inflammation. (2016)
  • Author(s): Yang S, Imamura Y, Jenkins RW, Canadas I, Kitajima S, Aref A, Brannon A, Oki E, Castoreno A, Zhu Z, Thai T, Reibel J, Qian Z, Ogino S, Wong KK, Baba H, Kimmelman AC, Pasca Di Magliano M, Barbie DA.
  • Journal Title: Cancer Immunol Res. Volume: 4 Pages: 520-530
  • Peer Reviewed / Int'l Joint Research
• [Presentation] MSI-low is an intermediate type between MSI-high and MSS in esophagogastric junction adenocarcinoma. (2019)
  • Author(s): Imamura Y, Toihata T, Takamatsu M, Tanaka N, Mine S, Mori S, Oki E, Morita M, Baba H, Sano T, Watanabe M
  • Organizer: Gastrointestinal Cancers Symposium (ASCO-GI 2019)
  • Int'l Joint Research
• [Presentation] 食道胃接合部腺癌の腫瘍占居別molecular statusの特徴 (2018)
  • Author(s): 今村裕、問端輔、峯真司、比企直樹、沖英次、森田勝、前原喜彦、馬場秀夫、佐野武、渡邊雅之
  • Organizer: 第73回日本消化器外科学会総会
• [Presentation] Significance of Tumor-infiltrating CD8+and FOXP3+ T cells in esophagogastricjunction adenocarcinoma. (2018)
  • Author(s): 問端輔、今村裕、上月亮太郎、岡村明彦、湯田匡美、峯真司、比企直樹、佐野武、渡邊雅之
  • Organizer: 第72回日本食道学会学術集会
• [Presentation] 食道胃接合部腺癌に対する胸腹部アプローチの比較検討 (2018)
  • Author(s): 今村 裕
  • Organizer: 第30回 日本内視鏡外科学会総会
• [Presentation] 食道胃接合部腺癌の腫瘍占居部位とmolecular statusの検討 (2018)
  • Author(s): 今村 裕
  • Organizer: 第14回 日本消化管学会総会
• [Presentation] Molecular status changes according to tumor location in EGJ adenocarcinoma (2018)
  • Author(s): Yu Imamura
  • Organizer: The 11th International Gastrointestinal Consensus Symposium
  • Int'l Joint Research
• [Presentation] 食道胃接合部腺癌におけるマイクロサテライト不安定性の検討 (2017)
  • Author(s): 今村 裕
  • Organizer: 第117回日本外科学会総会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2017-04-27
• [Presentation] 食道胃接合部腺癌におけるマイクロサテライト不安定性の特徴と予後解析 (2017)
  • Author(s): 今村 裕
  • Organizer: 第89回日本胃癌学会総会
  • Place of Presentation: 広島国際会議場
  • Year and Date: 2017-03-08
• [Presentation] 食道胃接合部腺癌におけるマイクロサテライト不安定性の検討 (2017)
  • Author(s): 今村 裕
  • Organizer: 第117回外科学会総会
• [Presentation] 食道胃接合部腺癌は腫瘍占居部位によりheterogeneousなgenetic statusを呈する (2017)
  • Author(s): 今村 裕
  • Organizer: 第72回 日本消化器外科学会総会
• [Funded Workshop] Clinical Congress American College of Surgeons (2016)
  • Place of Presentation: Washington DC, USA
  • Year and Date: 2016-10-16