Abstract 1850: CDK inhibitor PHA-848125 preferentially inhibits proliferation of triple negative breast cancer and synergizes with cisplatin

Abstract

Abstract Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), is highly aggressive with a poor prognosis as it lacks targeted therapies. Several inhibitors of the cyclin-dependent kinase 4 and 6 (CDK4/6) have been approved by the FDA for the treatment of ER-positive breast cancer. However, the effectiveness of these inhibitors against TNBC tumors is less than expected. Here, we tested the efficacy of PHA-848125, a potent ATP-competitive CDK2 inhibitor, on a panel of breast cancer cell lines showing a selective impaired proliferation in TNBC cells (IC50 of ER-positive MCF7 cells: 25.9 μM vs. IC50 of TNBC MDA-MB-231 cells: 430.8 nM). TNBC cells treated with PHA-848125 exhibited effects consistent with CDK2 inhibition, including G1 cell cycle arrest and reduced phosphorylation levels of the retinoblastoma protein (pRB) and CDK2. Interestingly, PHA-848125 was also effective against pRB-null TNBC cell lines, unlike other approved CDK inhibitors. Oral administration of PHA-848125 to TNBC xenograft mice and MMTV-PyMT transgenic mice impaired both tumor growth and metastasis at a tolerable dose (40 mg/kg), but not in ER-positive xenograft mice. A combination treatment of PHA-848125 and cisplatin inhibited tumor growth and induced apoptosis synergistically in vitro and in vivo. Thus, our preclinical experiments set the rationale for the clinical evaluation of PHA-848125, either alone or in combination with cisplatin, for the treatment of TNBC. Citation Format: Douglas G. Cheung, Marta Buzzetti, Carlo M. Croce, Gianpiero di Leva. CDK inhibitor PHA-848125 preferentially inhibits proliferation of triple negative breast cancer and synergizes with cisplatin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1850.