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Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors.

ABSTRACT: The present studies sought to define whether checkpoint kinase 1 (CHK1) inhibitors and poly(ADP-ribose) polymerase 1 (PARP1) inhibitors interact in vitro and in vivo to kill breast cancer cells. PARP1 and CHK1 inhibitors interacted to kill estrogen receptor (ER)+, ER+ fulvestrant-resistant, HER2+, or triple-negative mammary carcinoma cells in a manner that was not apparently affected by phosphatase and tensin homolog deleted on chromosome 10 functional status. Expression of dominant-negative CHK1 enhanced and overexpression of wild-type CHK1 suppressed the toxicity of PARP1 inhibitors in a dose-dependent fashion. Knockdown 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 demonstrate that the combination of PARP1 and CHK1 inhibitors has antitumor activity in vivo against multiple mammary tumor types and that translation of this approach could prove to be a useful anticancer therapeutic approach.

SUBMITTER: Tang Y

PROVIDER: S-EPMC3400842 | biostudies-other | 2012 Aug

REPOSITORIES: biostudies-other

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Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors.

Tang Yong Y Hamed Hossein A HA Poklepovic Andrew A Dai Yun Y Grant Steven S Dent Paul P

Molecular pharmacology 20120517 2

The present studies sought to define whether checkpoint kinase 1 (CHK1) inhibitors and poly(ADP-ribose) polymerase 1 (PARP1) inhibitors interact in vitro and in vivo to kill breast cancer cells. PARP1 and CHK1 inhibitors interacted to kill estrogen receptor (ER)+, ER+ fulvestrant-resistant, HER2+, or triple-negative mammary carcinoma cells in a manner that was not apparently affected by phosphatase and tensin homolog deleted on chromosome 10 functional status. Expression of dominant-negative CHK ...[more]

PMID: 22596349

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Project description:Poly(ADP-ribose) polymerases (PARPs) are involved in many aspects of the cellular response to various forms of damage. PARP-1 and PARP-2, the most abundant PARPs, are central to the response to specific types of DNA damage, especially single-strand breaks. Inhibition of PARP activity may sensitize the cell to exogenous agents such as chemotherapy and radiation. In circumstances where rescue pathways are deficient, particularly the homologous recombination (HR)-directed DNA repair pathway, inhibition of PARP may result in "synthetic lethality." BRCA mutation-associated breast cancers are a paradigm of HR-directed repair deficient tumors. Early clinical trials have demonstrated significant activity of single-agent PARP inhibitors in BRCA-deficient breast and ovarian cancer. Because of phenotypic similarities between some "triple-negative" breast cancers (TNBC) and the most prevalent type of breast cancer seen in BRCA1 mutation carriers, some have hypothesized that TNBC might also be specifically sensitive to PARP inhibition. The activity of single-agent PARP inhibitors in TNBC has not been reported. One trial did suggest significant enhancement of the activity of platinum-based combination chemotherapy, without incremental toxicity. These studies indicate that PARP inhibition is an exciting new approach to the treatment of breast cancers in women with underlying BRCA mutations and possibly in sporadic cancers with defects in HR-directed repair. Future studies will be necessary to determine whether the effectiveness of PARP inhibitors in nonhereditary cancer requires an underlying HR defect or whether these agents may improve the activity of conventional chemotherapy by other means. In addition, studies will be required to determine whether PARP inhibitors may induce synthetic lethality in tumors with defects in pathways other than the BRCA-dependent DNA repair pathway. If either or both of these prove to be the case, then PARP inhibition may benefit a wide spectrum of cancer patients.

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Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors.

Publications

Poly(ADP-ribose) polymerase 1 modulates the lethality of CHK1 inhibitors in mammary tumors.

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