PT - JOURNAL ARTICLE AU - Yong Tang AU - Hossein A Hamed AU - Andrew Poklepovic AU - Yun Dai AU - Steven Grant AU - Paul Dent TI - PARP1 Modulates the Lethality of CHK1 Inhibitors in Mammary Tumors. AID - 10.1124/mol.112.078907 DP - 2012 May 17 TA - Molecular Pharmacology PG - mol.112.078907 4099 - http://molpharm.aspetjournals.org/content/early/2012/05/17/mol.112.078907.short 4100 - http://molpharm.aspetjournals.org/content/early/2012/05/17/mol.112.078907.full AB - The present studies sought to define whether CHK1 inhibitors and PARP1 inhibitors interact in vitro and in vivo to kill breast cancer cells. PARP1 and CHK1 inhibitors interacted to kill ER+; ER+ fulvestrant resistant; HER2+; or triple negative mammary carcinoma cells in a manner that was not apparently impacted by PTEN functional status. Expression of dominant negative CHK1 enhanced, and over-expression of wild type CHK1 suppressed, the toxicity of PARP1 inhibitors in a dose dependent fashion. Knock down of PARP1 enhanced the lethality of CHK1 inhibitors in a dose dependent fashion. PARP1 and CHK1 inhibitors interacted in vivo both to suppress the growth of large established tumors and to suppress the growth of smaller developing tumors; the combination enhanced animal survival. PARP1 and CHK1 inhibitors profoundly radiosensitized cells in vitro and in vivo. In conclusion, our data demonstrates that the combination of PARP1 and CHK1 inhibitors has anti-tumor activity in vivo against multiple mammary tumor types and that translation of this approach could prove a useful anti-cancer therapeutic approach.