CDK4/6 Inhibitor Palbociclib Induces Therapeutic Senescence in Melanoma Cells

The p16-cyclin D1-CDK4/6-Rb pathway is dysregulated in a large percentage of melanomas and has become an interesting target for the therapeutic treatment of this disease. CDK4 activation results in the inhibition of the retinoblastoma protein that leads to G1-S cell-cycle transition, and also phosphorylates other proteins that promote cell-cycle progression and inhibit apoptosis and senescence in the cell. It is thought that melanomas with activating events in the CDK4 pathway may become overly dependent on it, in which case inhibition of CDK4 would go beyond the induction of cell-cycle arrest to apoptosis and tumor regression.

In a study published in March of 2016, palbociclib, a specific CDK4/6 inhibitor, was shown to induce cell cycle arrest and eventual senescence in melanoma cells. Furthermore, palbociclib was found to maintain its effectiveness even in tumors resistant to vemurafenib, a specific BRAF(V600E) inhibitor. Vemurafenib has shown significant clinical efficacy in BRAF(V600E)-positive melanomas, but rapid resistance by the tumor to the compound has hampered its impact.

These findings suggest that palbociclib may be a promising therapeutic for the treatment of melanoma, and that a treatment path involving vemurafenib followed by palbociclib may yield an effective treatment for the vemurafenib-resistant metastatic disease. The CDK4/6 pathway and its inhibitors will continue to be investigated for their role in melanoma and tumor development and suppression.

LKT Labs supplies research grade palbociclib and vemurafenib, in addition to other CDK4/6 inhibitors.

P0244 Palbociclib Hydrochloride
R5774 Roscovitine
O4556 Olomoucine
I5212 Indirubin

Sheppard KE, McArthur GA. The cell-cycle regulator CDK4: an emerging therapeutic target in melanoma. Clin Cancer Res. 2013 Oct 1;19(19):5320-8. doi: 10.1158/1078-0432.CCR-13-0259. PMID: 24089445

Yoshida A, Lee EK, Diehl JA. Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6. Cancer Res. 2016 May 15;76(10):2990-3002. doi: 10.1158/0008-5472.CAN-15-2931. Epub 2016 Mar 17. PMID: 26988987