title: Targeting cell cycle and hormone receptor pathways in cancer.
abstract: The cyclin/cyclin-dependent kinase (CDK)/retinoblastoma (RB)-axis is a critical modulator of cell cycle entry and is aberrant in many human cancers. New nodes of therapeutic intervention are needed that can delay or combat the onset of malignancies. The antitumor properties and mechanistic functions of PD-0332991 (PD; a potent and selective CDK4/6 inhibitor) were investigated using human prostate cancer (PCa) models and primary tumors. PD significantly impaired the capacity of PCa cells to proliferate by promoting a robust G1-arrest. Accordingly, key regulators of the G1-S cell cycle transition were modulated including G1 cyclins D, E and A. Subsequent investigation demonstrated the ability of PD to function in the presence of existing hormone-based regimens and to cooperate with ionizing radiation to further suppress cellular growth. Importantly, it was determined that PD is a critical mediator of PD action. The anti-proliferative impact of CDK4/6 inhibition was revealed through reduced proliferation and delayed growth using PCa cell xenografts. Finally, first-in-field effects of PD on proliferation were observed in primary human prostatectomy tumor tissue explants. This study shows that selective CDK4/6 inhibition, using PD either as a single-agent or in combination, hinders key proliferative pathways necessary for disease progression and that RB status is a critical prognostic determinant for therapeutic efficacy. Combined, these pre-clinical findings identify selective targeting of CDK4/6 as a bona fide therapeutic target in both early stage and advanced PCa and underscore the benefit of personalized medicine to enhance treatment response.
authors.affiliation: Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: C E S
authors.initials: CE
authors.lastname: Comstock
authors.forename: M A
authors.initials: MA
authors.lastname: Augello
authors.forename: J F
authors.initials: JF
authors.lastname: Goodwin
authors.forename: R
authors.initials: R
authors.lastname: de Leeuw
authors.forename: M J
authors.initials: MJ
authors.lastname: Schiewer
authors.forename: W F
authors.initials: WF
authors.lastname: Ostrander
authors.forename: R A
authors.initials: RA
authors.lastname: Burkhart
authors.forename: A K
authors.initials: AK
authors.lastname: McClendon
authors.forename: P A
authors.initials: PA
authors.lastname: McCue
authors.forename: E J
authors.initials: EJ
authors.lastname: Trabulsi
authors.forename: C D
authors.initials: CD
authors.lastname: Lallas
authors.forename: L G
authors.initials: LG
authors.lastname: Gomella
authors.forename: M M
authors.initials: MM
authors.lastname: Centenera
authors.forename: J R
authors.initials: JR
authors.lastname: Brody
authors.forename: L M
authors.initials: LM
authors.lastname: Butler
authors.forename: W D
authors.initials: WD
authors.lastname: Tilley
authors.forename: K E
authors.initials: KE
authors.lastname: Knudsen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors; D005240:Feasibility Studies; D006801:Humans; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000378:metabolism*; D012175:Retinoblastoma / Q000188:drug therapy / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011944:Receptors, Androgen; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib