Targeting CDK1 and MEK/ERK Overcomes Apoptotic Resistance in BRAF Mutated human Colorectal Cancer
Menée sur des lignées cellulaires de cancer colorectal avec mutation V600E du gène BRAF, cette étude met en évidence l'intérêt de cibler la kinase CDK1 et la voie de signalisation MEK/ERK pour lever la résistance des cellules cancéreuses à l'apoptose
The BRAFV600E mutation occurs in ~8% of human colorectal cancers (CRCs) and is associated with therapeutic resistance that is due, in part, to re-activation of MEK/ERK signaling cascade. Recently, pathway analysis identified cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E CRCs. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of MEK inhibition in BRAFV600E CRC cells. BRAFV600E CRC cell lines expressing CDK1 were sensitized to apoptosis upon siRNA knockdown or small-molecule inhibition with RO-3306 (CDK1 inhibitor) or dinaciclib (CDK1,2,5,9 inhibitor). Combination of RO-3306 or dinaciclib with cobimetinib (MEK inhibitor) cooperatively enhanced apoptosis and reduced clonogenic survival vs monotherapy. Cells isogenic or ectopic for BRAFV600E displayed resistance to CDK1 inhibitors, as did cells with constitutively active MEK. CDK1 inhibitors induced a CASP8-dependent apoptosis shown by caspase-8 restoration in deficient NB7 cells that enhanced dinaciclib-induced CASP3 cleavage. CDK inhibitors suppressed pro-CASP8 phosphorylation at S387, as shown by drug withdrawal, that restored p-S387 and increased mitosis. In a CRC xenograft model, dinaciclib plus cobimetinib produced significantly greater tumor growth inhibition in association with a caspase-dependent apoptosis vs either drug alone. The Cancer Genome Atlas (TCGA) transcriptomic dataset revealed overexpression of CDK1 in human CRCs vs normal colon. These data establish CDK1 as a novel mediator of apoptosis resistance in BRAFV600E CRCs whose combined targeting with a MEK/ERK inhibitor represents an effective therapeutic strategy. Implications: CDK1 is a novel mediator of apoptosis resistance in BRAFV600E colorectal cancers whose dual targeting with a MEK inhibitor may be therapeutically effective.