The BRAFV600E mutation occurs in approximately 8% of human
colorectal cancers and is associated with therapeutic resistance that is due, in part, to reactivation of
MEK/ERK signaling cascade. Recently, pathway analysis identified
cyclin-dependent kinase 1 (CDK1) upregulation in a subset of human BRAFV600E
colorectal cancers. Therefore, it was determined whether CDK1 antagonism enhances the efficacy of
MEK inhibition in BRAFV600E
colorectal cancer cells. BRAFV600E
colorectal cancer 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 inhibitors). Combination of
RO-3306 or
dinaciclib with
cobimetinib (
MEK inhibitor) cooperatively enhanced apoptosis and reduced clonogenic survival versus monotherapy. Cells isogenic or ectopic for BRAFV600E displayed resistance to CDK1 inhibitors, as did cells with ectopic expression of 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, which restored p-S387 and increased mitosis. In a
colorectal cancer xenograft model,
dinaciclib plus
cobimetinib produced significantly greater
tumor growth inhibition in association with a caspase-dependent apoptosis versus either drug alone. The
Cancer Genome Atlas (TCGA) transcriptomic dataset revealed overexpression of CDK1 in human
colorectal cancers versus normal colon. Together, these data establish CDK1 as a novel mediator of apoptosis resistance in BRAFV600E
colorectal cancers 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. Mol
Cancer Res; 16(3); 378-89. ©2017 AACR.