Palbociclib synergizes with BRAF and MEK inhibitors in treatment naïve melanoma but not after the development of BRAF inhibitor resistance

Abstract

Increased CDK4 activity occurs in the majority of melanomas and CDK4/6 inhibitors in combination with BRAF and MEK inhibitors are currently in clinical trials for the treatment of melanoma. We hypothesize that the timing of the addition of CDK4/6 inhibitors to the current BRAF and MEK inhibitor regime will impact on the efficacy of this triplet drug combination. The efficacy of BRAF, MEK and CDK4/6 inhibitors as single agents and in combination was assessed in human BRAF mutant cell lines that were treatment naïve, BRAF inhibitor tolerant or had acquired resistance to BRAF inhibitors. Xenograft studies were then performed to test the in vivo efficacy of the BRAF and CDK4/6 inhibitor combination. Melanoma cells that had developed early reversible tolerance or acquired resistance to BRAF inhibition remained sensitive to palbociclib. In drug-tolerant cells, the efficacy of the combination of palbociclib with BRAF and/or MEK inhibitors was equivalent to single agent palbociclib. Similarly, acquired BRAF inhibitor resistance cells lost efficacy to the palbociclib and BRAF combination. In contrast, upfront treatment of melanoma cells with palbociclib in combination with BRAF and/or MEK inhibitors induced either cell death or senescence and was superior to a BRAF plus MEK inhibitor combination. In vivo palbociclib plus BRAF inhibitor induced rapid and sustained tumor regression without the development of therapy resistance. In summary, upfront dual targeting of CDK4/6 and mutant BRAF signaling enables tumor cells to evade resistance to monotherapy and is required for robust and sustained tumor regression. Melanoma patients whose tumors have acquired resistance to BRAF inhibition are less likely to have favorable responses to subsequent treatment with the triplet combination of BRAF, MEK and CDK4/6 inhibitors.

Mechanisms of Acquired BRAF Inhibitor Resistance in Melanoma: A Systematic Review

“…One such change is upregulation of the cell cycle genes CDK6 and CCND1 [ 89 ]. This appears to open up the possibility of using CDK inhibitors to overcome resistance; preclinical data indicate that adding palbociclib to treatment with BRAF inhibitors and/or MEK inhibitors prevented resistance development in treatment-naïve melanoma cells and animal models, but did not overcome resistance in cells and animals with acquired BRAF inhibitor resistance [ 90 ].…”

The dynamics of ERK signaling in melanoma, and the response to BRAF or MEK inhibition, are cell cycle dependent

“…Our data also provide rationale for using CDK4/6 inhibitors in combination with BRAF or MEK inhibitors, as the number of cells driven into an ERK low quiescent-like by Dabrafenib or Binimetinib in combination with Palbociclib was greater than following treatment by any single agent. Indeed, such combinations have proven effective in KRAS mutant melanoma, colorectal cancer and Non-small cell lung cancer (94,95,96,97,98).…”

Current Molecular Markers of Melanoma and Treatment Targets

“…Maintaining long-term response is difficult, with just 20% of patients in one study remaining progression free [234]. Ongoing research is investigating the addition of CDK, MAPK, or immune checkpoint inhibitors to combat resistance [231,235,236]. Recently, Misek et al identified RhoA GTPases as a potential pathway for BRAF resistance and that inhibition of the pathway by Rho kinase (ROCK) inhibitors promotes resensitization to BRAF-targeting therapy [237].…”