チロシンキナーゼ阻害薬が引き起こす逆説的Src活性化とがん細胞増殖

• Published in: 日本薬理学会年会要旨集 p. 2-O-070
• Main Authors: 渡邊, 直樹, 樋口, 牧郎
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: cancer; inhibitor; oncogene protein; tyrosine kinase
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.95.0_2-O-070

Kinase inhibitors are potent cancer therapeutics. However, drug resistance often develops due to activation of accessory signaling pathways. Multi-target kinase inhibitors have thus been tried although their benefit and risk remain largely elusive. In this regard, we recently discovered an alerting mechanism by which anti-cancer drugs may become cancer-promoting agents (Cell Rep. 34:108876, 2021). We found that c-Src which normally locates on the plasma membrane, massively translocates to focal adhesions upon treatment with various tyrosine kinase inhibitors. Inhibitor-binding to the Src kinase domain causes the relief of autoinhibition, and released Src SH3 and SH2 domains bind focal adhesion kinase (FAK). At this step, Src is inactive. However, the low-affinity Src inhibitors such as AEE788, whose primary targets are EGFR and HER2, could be readily washed out from the Src-FAK complex, which leads to phosphorylation of FAK by Src. This triggers activation of Erk signaling cascade by recruiting Grb2 to focal adhesions. Furthermore, when MCF7 cells harbor drug-resistant mutations in SRC gene, even high-affinity inhibitors such as dasatinib and bosutinib induce the activation of the Src-FAK-Grb2-Erk signaling, paradoxically promoting cancer cell proliferation. We will discuss the implications of allosteric effects of ATP-competitive inhibitors and the paradoxical activation of cancer promoting signaling by kinase inhibitors.