Molecular mechanisms of paradoxical growth suppression by over activation of oncogene kinases
| Project/Area Number |
20K21554
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 50:Oncology and related fields
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
KATAYAMA Ryohei 公益財団法人がん研究会, がん化学療法センター 基礎研究部, 部長 (60435542)
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| Project Period (FY) |
2020-07-30 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Fiscal Year 2021: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
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| Keywords | キナーゼ / 過剰活性化 / 薬剤耐性 / 肺がん / ドライバーがん遺伝子 / がん |
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| Outline of Research at the Start |
本研究では、過剰すぎるDriver Oncogeneシグナル（ROS1やALK融合遺伝子陽性がんにおいてしばしば分子標的薬耐性獲得の際に認められるキナーゼ活性の亢進を起こす耐性変異）が引き起こすがん細胞のパラドキシカルな増殖抑制と細胞死誘導の詳細な分子メカニズムを明らかにするとともに、この現象を逆手に取った新規治療法を探索する。そのために、キナーゼの過剰活性化を発現誘導型ベクターを用いて人為的に強度を変えて誘導し、Driver Oncogeneからの増殖シグナルの強度が細胞増殖に与える影響を質的および量的の両方の面から解析する。
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| Outline of Final Research Achievements |
Various kinase inhibitors have been developed, and approved as molecular targeting drugs for cancer. However, in many cases, drug resistance inevitably occurs, and occasionally mutations that further increase kinase activity occurred. In such cases, we have found that the excess activation target kinase by temporally removing inhibitors inversely suppress cancer cell growth. In the present study, we tried to understand the mechanism of excessive kinase activity induced growth suppression to find new potential therapeutic targets. As a result, we found that several ALK-positive lung cancers that have developed resistance to therapy actually show excessive kinase activity, and also find that a certain factor plays an important role in that process.
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| Academic Significance and Societal Importance of the Research Achievements |
キナーゼ阻害薬などの分子標的薬に対して耐性がん細胞が出現する際には、様々な変異や他のがん遺伝子の活性化などが生じる。この時薬剤が除去されると、もともとのドライバーがん遺伝子からのシグナルに加えて、耐性時に獲得したシグナルも加わり過剰な増殖シグナルとなる。このことががんの増殖にとって不利に働くことのメカニズムが本研究により少しずつ明らかになっており、また実際に患者検体からもこのような現象があることが判明しつつあることは、今後新たな治療戦略を見出す可能性につながり、学術的意義は高い。
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Report
(3 results)
Research Products
(28 results)
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[Journal Article] HER3 activation contributes toward the emergence of ALK inhibitor-tolerant cells in ALK-rearranged lung cancer with mesenchymal features.2022
Author(s)
Tanimura K, Yamada T, Okada K, Nakai K, Horinaka M, Katayama Y, Morimoto K, Ogura Y, Takeda T, Shiotsu S, Ichikawa K, Watanabe S, Morimoto Y, Iwasaku M, Kaneko Y, Uchino J, Taniguchi H, Yoneda K, Matoba S, Sakai T, Uehara H, Yano S, Kusaba T, Katayama R, Takayama K.
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Journal Title
NPJ Precis Oncol.
Volume: 6
Issue: 1
Pages: 5-5
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer2021
Author(s)
Mizuta Hayato、Okada Koutaroh、Araki Mitsugu、Adachi Jun、Takemoto Ai、Kutkowska Justyna、Maruyama Kohei、Friboulet Luc、Katayama Kazuhiro、Ma Biao、Sasakura Yoko、Sagae Yukari、Kukimoto-Niino Mutsuko、Shirouzu Mikako、Takagi Satoshi、Simizu Siro、Nishio Makoto、Okuno Yasushi、Fujita Naoya、Katayama Ryohei, et al
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Journal Title
Nature Communications
Volume: 12
Issue: 1
Pages: 1261-1261
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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