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Do inhibitors targeted against mutant oncogenic kinases act via kinase degradation-induced immune activation?

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Söding,  J.
Research Group of Computational Biology, MPI for Biophysical Chemistry, Max Planck Society;

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Citation

Söding, J. (2021). Do inhibitors targeted against mutant oncogenic kinases act via kinase degradation-induced immune activation?. Unpublished Manuscript.


Cite as: http://hdl.handle.net/21.11116/0000-0009-5309-0
Abstract
Targeted cancer therapies by small-molecule inhibitors of receptor tyrosine and other kinases have achieved great success in recent years. Most targeted medications specifically inhibit a protein kinase mutated in the patient's tumor. Although many possible mechanisms have been investigated, the drugs' astounding efficacies are not well understood. We propose a unifying mechanism of action. Strong binding by the inhibitor could lead to increased ubiquitination and degradation by the proteasome, boosting the presentation of kinase-associated neoantigen peptides. This would facilitate tumor cell recognition by T cells, leading to a sustained immune attack. The model suggests that the as yet inevitable failure to shrink tumors further after a few months might be caused by a transition to chronic inflammation. If true, the model has a multitude of implications for cancer and clinical research.