Targeting Cdk4/6 in combination therapy of chemoresistant multiple myeloma

Abstract

8503 Background: Deregulation of Cdk4 or Cdk6 is a hallmark in cancer. However, conventional cancer therapy centers on empirical cytotoxic killing. Targeting the cell cycle with broad-spectrum inhibitors has proven ineffective so far due to cross- reactivity with cell survival and the transcriptional machinery. In myeloma, over-expression of Cdk4-cyclin D1 or Cdk6-cyclin D2 predisposes primary bone marrow (BM) myeloma cells to proliferation in vivo. Conversely, silencing Cdk4/6 by its physiologic inhibitor, p18INK4c, is required for cell cycle termination during the generation of normal plasma cells. Targeting Cdk4/6, therefore, represents a rational strategy to control disease progression and drug resistance in myeloma. Methods: An orally bioactive, small molecule PD 0332991 selectively and reversibly inhibits Cdk4/6 (IC50 ∼ 60 nM) in primary myeloma cells ex vivo. This leads to exclusive G1 cell cycle arrest unaccompanied by apoptosis by BrdU labeling and apoptotic assays. Results: By inducing synchronous S phase entry upon release of G1 block or prolonging G1 arrest, inhibition of Cdk4/6 by PD 0332991 profoundly sensitizes primary myeloma cells to killing by proteasome inhibitors bortezomib and NPI-0052, or dexamethasone. Sequential treatments with PD 0332991 and bortezomib rapidly reduces tumor burden in animal models. Importantly, it overcomes chemoresistance in myeloma cells isolated from refractory relapse patients, despite stromal protection. Synergistic killing of myeloma cells lies in induction of cell cycle-specific mitochondria depolarization. Base On this basis and a favorable outcome of Phase I clinical trial, a Phase I/II PD 0332991-bortezomib clinical trial for myeloma is in progress. Conclusion: Targeting Cdk4/6 by PD 0332991 in combination with a selective cytotoxic agent represents a new class of promising cell cycle-based therapy in myeloma, and possibly other cancers. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Ortho Biotech Amgen, Merck, Millennium, Novartis Johnson & Johnson MMRF, NIH/NIAMS, Ortho Biotech, VA Merit Review