Simak Ali: CDK7 Mutation Drives Resistance to Samuraciclib
Simak Ali, Professor of Molecular Endocrine Oncology at Imperial College London, shared a post on LinkedIn:
“CDK selective inhibitors are becoming established as important cancer drugs. Identifying mechanisms of response and resistance are critical for most appropriate use of these drugs. Using a clinical inhibitor of CDK7 samuraciclib, we show that a single base change in the CDK7 gene, resulting in a one amino acid change, can cause resistance to ATP-competitive CDK7i like samuraciclib. We show that the mutation permits ATP-dependent activity of the mutant CDK7 but reduces binding to ATP-competitive CDK7i.
Remarkably, the mutated residue is absolutely conserved in all CDKs and mutation of this residue in CDK4 reduced sensitivity to CDK4/6 inhibitors such as palbociclib that are used for ER+ breast cancer treatment. CDK12 inhibitors were similarly reduced in sensitivity by mutation of CDK12.
Our findings have implications for patient selection and identify the need for CDK mutation monitoring in treated patients and possibilities for treatment switching.
My thanks to the super efforts especially of Chun Fui Lai and Victoria Cushing, with Ellen Olden, Charlotte Bevan, charles coombes, Basil Greber, Laki (Lakjaya) Buluwela and funding from Prostate Cancer UK.”
Title: Resistance to CDK7 inhibitors directed by acquired mutation of a conserved residue in cancer cells
Authors: Chun-Fui Lai, Victoria I Cushing, Ellen Olden, Charlotte L Bevan, R Charles Coombes, Basil J Greber, Laki Buluwela, Simak Ali
Read The Full Article at EMBO.
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