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A Novel Therapeutic Combination Using PD 0332991 and Bortezomib: Study in the 5T33MM Myeloma Model

¹ Department of Pathology and ² Graduate Program in Immunology and Microbial Pathogenesis, Weill Medical College of Cornell University, New York, New York; ³ Vrije Universiteit Brussels, Laarbeeklaan 103, Brussels, Belgium; and ⁴ Pfizer Global Research and Development, Ann Arbor, Michigan, and San Diego, California

Requests for reprints: Selina Chen-Kiang, Department of Pathology, Weill Medical College of Cornell University, 1300 York Avenue, C314, New York, NY 10021. Phone: 212-746-6440; Fax: 212-746-7996; E-mail: sckiang{at}med.cornell.edu.

Key Words: Cdk4 • Cdk6 • p27^Kip1 • p18^INK4c • cyclin D2 • Blimp-1 • Bcl-6

Multiple myeloma (MM) remains incurable partly because no effective cell cycle–based therapy has been available to both control tumor cell proliferation and synergize with cytotoxic killing. PD 0332991 is an orally active small molecule that potently and specifically inhibits Cdk4 and Cdk6. It has been shown to induce rapid G₁ cell cycle arrest in primary human myeloma cells and suppress tumor growth in xenograft models. To improve therapeutic targeting of myeloma progression, we combined tumor suppression by PD 0332991 with cytotoxic killing by bortezomib, a proteasome inhibitor widely used in myeloma treatment, in the immunocompetent 5T33MM myeloma model. We show that 5T33MM tumor cells proliferate aggressively in vivo due to expression of cyclin D2, elevation of Cdk4, and impaired p27^Kip1 expression, despite inhibition of Cdk4/6 by p18^INK4c and the maintenance of a normal plasma cell transcription program. PD 0332991 potently inhibits Cdk4/6-specific phosphorylation of Rb and cell cycle progression through G₁ in aggressively proliferating primary 5T33MM cells, in vivo and ex vivo. This leads to tumor suppression and a significant improvement in survival. Moreover, induction of G₁ arrest by PD 0332991 sensitizes 5T33MM tumor cells to killing by bortezomib. Inhibition of Cdk4/6 by PD 0332991, therefore, effectively controls myeloma tumor expansion and sensitizes tumor cells to bortezomib killing in the presence of an intact immune system, thereby representing a novel and promising cell cycle–based combination therapy. [Cancer Res 2008;68(14):5519–23]