RT Journal Article
SR Electronic
T1 PARP1 Modulates the Lethality of CHK1 Inhibitors in Mammary Tumors.
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.078907
DO 10.1124/mol.112.078907
A1 Yong Tang
A1 Hossein A Hamed
A1 Andrew Poklepovic
A1 Yun Dai
A1 Steven Grant
A1 Paul Dent
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/05/17/mol.112.078907.abstract
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.