Poster abstracts
Poster number 9 submitted by Douglas Cheung
Inhibition of CDKs with PHA-848125 impairs estrogen receptor negative breast cancer progression and metastasis
Douglas Cheung (Molecular, Cellular, and Developmental Biology Graduate Program, The Ohio State University), Gianpiero di Leva, Matteo Fassan, Claudia Piovan (Department of Cancer Biology and Genetics, The Ohio State University), Krishna Patel, Arpan Kumar, Dorothee Wernicke, Stefano Volinia (Department of Cancer Biology and Genetics, The Ohio State University), Marina Ciomei (Business Unit Oncology, Nerviano Medical Sciences), Michela Garofalo (Transcriptional Networks in Lung Cancer, CRUK Manchester Institute), Carlo M. Croce (Department of Cancer Biology and Genetics, The Ohio State University)
Abstract:
The cell cycle is frequently deregulated in breast cancer, allowing rapid cell proliferation and tumor growth. The cell cycle is tightly regulated by cyclins and cyclin-dependent kinases (CDKs). We show here that estrogen receptor (ER) negative breast cancer cells are more sensitive to the multi-CDK inhibitor PHA-848125, which has the highest selectivity for CDK2, than ER positive breast cancer cells. PHA-848125 treatment of ER negative cells caused G1 cell cycle arrest and a reduction of phosphorylation of the retinoblastoma protein (RB), confirming the CDK2 inhibitory effect of the drug. Oral administration of PHA-848125 to mice bearing MDA-MB-231 xenograft TNBC tumors resulted in an inhibition of tumor growth and metastatic progression at tolerable doses. However, PHA-848125 had no effect in mice bearing MCF-7 ER-positive tumors. PHA-848125 treatment reduced both the sizes and the numbers of tumors in MMTV-PyMT mice. Our preclinical experiments therefore set the rationale for the clinical evaluation of PHA-848125 in the treatment of ER-negative breast cancer.
Keywords: cell cycle, CDK, breast cancer