PARP Inhibitors Synergize With Loss of Checkpoint Control to Kill Mammary Carcinoma Cells

摘要

The funded studies were to determine whether PARP1 and CHK1 inhibitors interact in vitro and in vivo to kill mammary carcinoma cells. We published the first portion of our studies in November 2010. Using primarily ER+ breast cancer cells we found that transient expression of dominant-negative CHK1 raised basal ERK1/2 activity and prevented CHK1 inhibitors from activating ERK1/2. CHK1 inhibitors modestly increased the levels of PARP1 ADP ribosylation and molecular or small-molecule inhibition of PARP1 blocked CHK1 inhibitor- stimulated histone H2AX phosphorylation and activation of ERK1/2. Multiple CHK1 inhibitors interacted in a greater than additive fashion with multiple PARP1 inhibitors to cause transformed cell-killing in shortterm viability assays and synergistically killed tumor cells in colony-formation assays. Subsequent unpublished studies demonstrated in vitro and in vivo that this drug combination kills triple negative breast cancer cells in a greater than additive fashion and does so regardless of tumor cell PTEN status. Thus, PARP1 plays an important role in regulating the ability of CHK1 inhibitors to activate ERK1/2 and the DNA damage response. An inability of PARP1 to modulate this response results in transformed cell death mediated through the intrinsic apoptosis pathway.