The tyrosine kinase inhibitor GNF-7 targets senescent cells through allosteric activation of GCN2.
Lopez-Pernas, G.; Murga, M.; Ahmed, W.; Haggblad, M.; Jimenez-Ortega, E.; Serrano, A. G.; Cardona, C.; Lopez-Prieto, M.; Fisicaro, S.; Mota-Pino, J.; Navarro-Gonzalez, B.; Zarzuela, E.; Anton, M. E.; Lidemalm, L.; Matinez, S.; Isasa, M.; Pastor, J.; Fernandez-Leiro, R.; Huhn, D.; Fernandez-Capetillo, O.
Show abstract
The one-two-punch approach refers to the sequential administration of two different chemotherapies, the second of which targets cancer cells that resisted the initial treatment. To find such a second punch, we performed a chemical screen to find drugs that are preferentially toxic for cells with an activated DNA damage response (DDR). This screen identified the tyrosine kinase inhibitor GNF-7 as a top hit. Subsequent work revealed that GNF-7 is a potent senolytic, even when senescence is triggered by therapies that do not activate the DDR. Consistently, GNF-7 is highly efficacious to kill cancer cells previously treated with CDK4/6 inhibitors, including in patient-derived organoids and mouse xenografts. Surprisingly, the senolytic effect of GNF-7 is not mediated by the inhibition of a tyrosine kinase (TK), but rather by the activation of GCN2, an effect previously reported for other TK inhibitors. Together, our study reports the discovery of a novel senolytic agent that strongly synergizes with CDK4/6 inhibitors when applied sequentially and expands our understanding of the mechanisms behind the anticancer effects of TK inhibitors.
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