Research Paper Volume 9, Issue 12 pp 2695—2716

A hypothesis-driven approach identifies CDK4 and CDK6 inhibitors as candidate drugs for treatments of adrenocortical carcinomas

Figure 7. Pathways targeted by palbociclib in SW-13 and NCI-H295R cells. (a) In SW-13 cells palbociclib acts by inhibiting the kinase activity of CDK6 and leads to a decrease in phosphorylated Rb. E2F is then sequestered and cannot activate the transcription program necessary for the G1/S transition. In addition, palbociclib leads to a decrease of phosphorylated Ser9-GSK3β, resulting in GSK3β stabilization and consecutively to the degradation of β-catenin. Consequently, these events disturb the transcription program involved in inhibition of senescence, in cellular proliferation and in avoidance of apoptosis. (b) In NCIH295R cells palbociclib acts by inhibiting the kinase activity of CDK6. Since the cell line is Rb-/-, E2F activates the transcription program necessary for G1/S transition. Palbociclib lowers Ser9-GSK3β phosphorylation, increases its stability and ultimately induces β-catenin degradation. However, this cell line carries a heterozygous mutation in the CTNNB1 gene (p.S45P) that leads to a constitutively active form of β-catenin. Thus, only the non-mutated form of β-catenin is targeted by GSK3β that is stabilized by palbociclib.