Cell Rep 2021 Mar 23;3412:108876. doi: 10.1016/j.celrep.2021.108876.

Paradoxical activation of c-Src as a drug-resistant mechanism.

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ATP-competitive inhibitors have been developed as promising anti-cancer agents. However, drug-resistance frequently occurs, and the underlying mechanisms are not fully understood. Here, we show that the activation of c-Src and its downstream phosphorylation cascade can be paradoxically induced by Src-targeted and RTK-targeted kinase inhibitors. We reveal that inhibitor binding induces a conformational change in c-Src, leading to the association of the active form c-Src with focal adhesion kinase (FAK). Reduction of the inhibitor concentration results in the dissociation of inhibitors from the c-Src-FAK complex, which allows c-Src to phosphorylate FAK and initiate FAK-Grb2-mediated Erk signaling. Furthermore, a drug-resistant mutation in c-Src, which reduces the affinity of inhibitors for c-Src, converts Src inhibitors into facilitators of cell proliferation by enhancing the phosphorylation of FAK and Erk in c-Src-mutated cells. Our data thus reveal paradoxical enhancement of cell growth evoked by target-based kinase inhibitors, providing potentially important clues for the future development of effective and safe cancer treatment.

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Species referenced: Xenopus laevis
Genes referenced: grb2 mapk1 ptk2
GO keywords: ATP binding


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