PRJNA559517
The landscape of drug resistant CDK4/6 mutants
These saturating mutagenesis screens of CDK4 and CDK6 resistance to palbociclib were part of a larger study defining the landscape of ATP-competitive inhibitor resistance residues in protein kinases. We utilized the structural conservation of protein kinase domains, the similar mechanism of action for ATP-competitive kinase inhibitors, and a systematic comparison of mutagenesis assays to prospectively identify common sites of drug resistance in kinases. To do this we perform hotspot analysis of 8 different mutagenesis screens for resistance to ATP-competitive inhibitors. Two screens, identifying CDK6 and CDK4 resistance to palbociclib, are novel saturating mutagenesis screens presented here for the first time and included in this submission; two screens are saturating mutagenesis screens previously reported by our group; and 4 screens are sub-saturating datasets obtained from the literature. Using this approach we identified multiple sites that drive drug resistance when mutated and validate them in an extended panel of kinases. Unexpectedly, we uncovered a common position where mutation leads to activation, and subsequently drug resistance in protein kinases. In the future, comparative mutagenic approaches such as those described here may be used to improve drug efficacy, support biological discovery of kinase targets, and potentially may help identify activating or drug-resistant mutants that arise in disease.