Palbociclib is a chemotherapy drug used to treat advanced breast cancers. In a phase 3 clinical trial, a combination of palbociclib and fulvestrant more than doubled median progression-free survival time in women with ER+, HER- breast cancer compared to fulvestrant alone. Palbociclib received accelerated approval from the FDA in 2015 for ER+ breast cancers, and in 2017 was approved for the treatment of HER2- breast cancers.
The cyclin-dependent kinases CDK4 and CDK6 cause cells to pass from the G1 phase to the S phase and divide. Palbociclib works by selectively inhibiting these kinases.
Recently, Miettinen et al. argued that palbociclib’s remarkable effectiveness against breast cancer can not be explained by CDK4 and CDK6 inhibition alone. They used a method called cellular thermal shift assay to investigate other targets of palbociclib within the cell. This assay measures changes in the thermal stability of proteins in living cells, which can be used to determine which proteins are bound or modified by the drug of interest.
Miettinen et al. found that palbociclib targets the proteasome in a breast cancer cell line. Palbociclib activates the proteasome by preventing the suppressor protein ECM29 from binding to it. The authors speculate that tightly regulated proteasome activity is required for cell division, so palbociclib’s activation of the proteasome could be another way that it treats breast cancer.
Miettinen TP, Peltier J, Hartlova A, Gierlinski M, Jansen VM, Trost M, Bjorklund M. Thermal proteome profiling of breast cancer cells reveals proteasomal activation by CDK4/6 inhibitor palbociclib. (2018). doi: 10.15252/embj.201798359.
