2022 Fiscal Year Final Research Report
Exploring receptor type tyrosine kinases regulating Hippo pathway for the treatment of patients with head and neck cancer
| Project/Area Number |
20K18477
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 57020:Oral pathobiological science-related
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| Research Institution | Hiroshima University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | YAP / Hippo経路 / AXL / EGFR / 口腔扁平上皮癌 / 頭頸部扁平上皮癌 / 肺腺癌 / EGFR阻害薬耐性 |
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| Outline of Final Research Achievements |
The objective of this study is to clarify the mechanism by which AXL regulates the Hippo pathway and confers resistance to EGFR inhbitors. Database analysis revealed that AXL is the RTK most relevant to the Hippo pathway. AXL inhibitor treatment increased YAP phosphorylation and reduced CTGF/CYR61 expression in HNSCC and LUAC cells highly expressing AXL. Co-immunoprecipitation assay demonstrated that EGFR and AXL form a heterodimer, and siRNA knockdown of AXL induced EGFR inactivation and reduced CTGF/CYR61 expression. LATS1/2 knockout by CRISPR/Cas9 system rescued the phenotype mentioned above. AXL heterodimerizes with EGFR and activates YAP through EGFR-MOB1 axis, thereby conferring resistance to EGFR inhibitors. This suggests that combination therapy with AXL inhibitors and EGFR inhibitors may be a novel cancer therapeutic approach targeting YAP.
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| Free Research Field |
口腔病理学
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| Academic Significance and Societal Importance of the Research Achievements |
頭頸部扁平上皮癌（HNSCC）で遺伝子増幅・過剰発現、あるいは肺腺癌（LUAC）で活性化変異しているEGFRが、がん遺伝子のYAPを活性化して増殖を促進することを以前見出していた。しかしEGFR阻害薬単剤では再発や耐性が問題となっており、別の遺伝子によるYAP再活性化が関与する可能性が示唆されていた。本研究の成果は、AXLによるYAP活性化およびEGFR阻害薬耐性を付与する機構を解明することで，EGFR阻害薬の耐性を解除するためにAXL阻害薬を併用する新たな治療法の可能性を見出した．将来的にHNSCCおよびLUACを示す患者の治療効果を改善し，生命予後の延長をもたらす点で臨床的にも重要である．
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