A research for gastrointestinal cancer treatment targeting EGFR-p53 pathway

• Project/Area Number: 18K07288
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: National Hospital Organization Shikoku Cancer Center (2020); University of Tsukuba (2018-2019)
• Principal Investigator: HYODO ICHINOSUKE 独立行政法人国立病院機構四国がんセンター(臨床研究センター), その他部局等, 医師 (60416469)
• Co-Investigator(Kenkyū-buntansha): 山本 祥之 筑波大学, 附属病院, 病院講師 (00649288)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: p53腫瘍抑制遺伝子 / p53

Outline of Final Research Achievements

Oncoprotein murine double minute homolog 2 (MDM2) and MDM4 cooperatively inhibit tumor-suppressor protein p53. Our previous study reported that the simultaneous inhibition of MDM2 and MDM4 using nutlin-3 (a small molecule inhibitor of MDM2-p53 interaction) and chimeric small interfering RNA with DNA-substituted seed arms (named chiMDM2 and chiMDM4) more potently activated p53 than the MDM2 or MDM4 inhibitor alone and synergistically augmented antitumor effects in various types of cancer cells with the wild-type TP53. Moreover, our study showed this time that the triple inhibition of MDM4, MDM2 and MEK exerted a potent antitumor effect in wild-type TP53 colon and gastric cancer cells with mutant KRAS. We have revealed simultaneous activation of p53 and inhibition of aberrant KRAS signaling may be a rational treatment strategy for gastrointestinal tumors.

Academic Significance and Societal Importance of the Research Achievements

多くのがん細胞の増殖因子シグナルは活性化されており、消化器癌ではKRAS変異によるEGFRシグナル増強が代表的である。今回の研究結果から同時性のEGFRシグナルの抑制とp53活性化の治療戦略は、KRAS変異を有するp53野生型消化器癌（胃癌、大腸癌）において有望であることが示唆された。KRAS変異は他のがん種においても高頻度に認められ、ここで示した治療戦略は多くのがん治療において貢献できる可能性を秘めている。

Research Products

• [Journal Article] MDM4 as a Prognostic Factor for Patients With Gastric Cancer With Low Expression of p53. (2021)
  • Author(s): Zhang X, Yamamoto Y, Wang X, Sato M, Imanishi M, Sugaya A, Hirose M, Endo S, Moriwaki T, Yamato K, Hyodo I
  • Journal Title: Anticancer Res. Volume: 41 Issue: 3 Pages: 1475-1483
  • DOI: 10.21873/anticanres.14906
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhanced G1 arrest and apoptosis via MDM4/MDM2 double knockdown and MEK inhibition in wild-type TP53 colon and gastric cancer cells with aberrant KRAS signaling (2021)
  • Author(s): Wang X, Yamamoto Y, Imanishi M, Zhang X, Sato M, Sugaya A, Hirose M, Endo S, Natori Y, Moriwaki T, Yamato K, Hyodo I
  • Journal Title: Oncology Letters Volume: -
  • Peer Reviewed / Open Access / Int'l Joint Research