Induction of Therapeutic Senescence in Vemurafenib-Resistant Melanoma by Extended Inhibition of CDK4/6

Abstract

Dysregulation of the p16-cyclin D1-CDK4/6-Rb pathway occurs frequently in melanoma; however, the therapeutic efficacy of CDK4/6 inhibition remains to be critically evaluated. We demonstrate that CDK4/6 inhibition inhibits melanoma progression through induction of senescence. Palbociclib, a specific CDK4/6 inhibitor, rapidly induces cell cycle arrest within 24 hours and continued exposure for 8 days or longer induces senescence. The induction of senescence correlates with inhibition of mTOR and more specifically mTORC1 signaling. Vemurafenib, a specific BRAF(V600E) inhibitor, has significant clinical efficacy in BRAF(V600E)-positive melanomas, but its impact is hampered by a rapid acquisition of resistance. Strikingly, we found that vemurafenib-resistant tumors remain sensitive to palbociclib, suggesting that initial treatment with vemurafenib followed by palbociclib with or without mTOR inhibitors might provide an avenue to overcome recurrence of vemurafenib-resistant metastatic disease. Taken together, these results support palbociclib as a promising therapeutic for treatment of melanoma. Cancer Res; 76(10); 2990-3002. ©2016 AACR.