Supplemental figure 1-983BR and 1205LuR are resistant to vemurafenib. Cell cycle analysis of 983B, 983BR, 1205Lu, and 1205LuR cells treated with or without vemurafenib for 2 days by FACS. Supplemental Fig. 2 Inhibition of mTOR signaling pathway is critical for palbociclib-induced senescence in 983BR vemurafenib resistant cells, related to Figure. 6. Supplemental Fig. 3 Overexpression of mTOR signaling overrides palbociclib-induced senescence in 983BR vemurafenib resistant cells, related to Figure. 7. Supplemental Fig. 4 Rb expression in palbociclib resistant cells. Supplemental Fig. 5 Rapamycin negatively regulates geroconversion in esophageal cancer cell lines (referred to in discussion). Supplemental Fig. 6 Palbociclib has no cytotoxicity in 983BR vemurafenib resistant cells.
ARTICLE 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 BRAFV600E inhibitor, has significant clinical efficacy in BRAFV600E-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.
