Over the last 20 years, attempts have been made to develop CDK inhibitors for clinical use. Flavopiridol (Alvocidib) was the first CDK inhibitor to enter clinical trials [17
]. Reports from several phase II studies damped the enthusiasm of some investigators [18
]. Another CDK inhibitor AT7519 developed by Astex Therapeutics Ltd [20
] did not meet the expectations of the research community as well. This first generation of CDK inhibitors are considered broad in spectrum of CDK targets, not selective for specific CDK(s). Lessons learned from earlier experiments with CDK inhibitors have led to the development of newer generations of CDK inhibitors targeting CDK4/6 activities in breast cancer [9
Palbociclib (PD0332991). Developed by Pfizer, Palbociclib inhibits cell proliferation in some breast cancer cell lines tested such as MCF7, T47D, ZR75-1 and some other non-breast cancer cell lines such as Colo-205 (Colon
) etc [21
]. Finn RS et al. later broadened the cell line spectrum to include some Her2 positive breast cancer lines. Palbociclib inhibited cell growth of Her2 positive breast cancer cell lines such as BT474, SKBR3, MDA-MB-361 etc. with concentrations in the nanomolar range [22
].The potent selective inhibitory activity of Palbociclib on CDK4/6 kinases is demonstrated in vivo in an erbB2 overexpressing transgenic mouse model in which Its inhibitory effects on erbB2-induced murine mammary tumors phenocopied the effect of conditional cyclin D1 knockout , namely it inhibited tumor progression and induced senescence of cancer cells [23
]. A phase II study combining Palbociclib and letrozole in the treatment of ER+/Her2- breast cancer yielded impressive results (2014 AACR abstract #CT101). A phase III trial using the same combination for ER+/Her2- breast cancer is underway. If the drug is eventually approved by FDA for the treatment of breast cancer, clinical trials using Palbociclib as a single agent or in combination with other approved drugs such as Herceptin for the treatment of Her2 positive breast cancer could be predicted in the near future.
There are some other CDK4/6 inhibitors in development such as LEE011, Developed by Novartis, and LY2835219, Developed by Eli Lilly [9
]. Both compounds are orally bioavailable
and both have the potential to be used in breast cancer treatment [24
]. Phase 1b/2 trials of LEE011 (NCT 01857193) and LY2835219 (NCT02057133, NCT02102490) are currently recruiting patients (http://clinicaltrials.org
). Which CDK4/6 inhibitor will eventually enter the market depending on the results of later clinical trials. The good news is that we are making progress in the field.