Rational Combination Therapy with PARP Inhibitors in Triple Negative Breast Cancer

三阴性乳腺癌（TNBC）是乳腺癌的一种亚型，经常复发和复发

Triple negative breast cancer (TNBC) is one subtype of breast cancer that frequently relapses and leads to worse outcome than patients with hormone receptor-positive subtypes. PARP is currently the most promising drug target for TNBC, and multiple PARP inhibitors (PARPi) have been developed and tested in clinical trials. Although PARPi show higher response rate in patients carrying BRCA mutations, there are still high percentage of BRCA mutations carried patients does not respond to PARPi. Thus, developing strategies to make PARPi treatment more effective and to identify biomarkers to stratify patients is critical. Our recent publication in Nature Medicine (2016) showed that in response to reactive oxygen species, c-Met interacts with and phosphorylates PARP1 at Y907. Moreover, we demonstrated that c-Met-mediated phosphorylation is critical for PARPi resistance, and that c-Met inhibitors sensitize TNBC cells to PARPi. The long-term goal of our research is to develop the effective therapeutic strategies for TNBC. To this end, we will seek the novel biomarkers and treatment strategies to improve the efficacy of PARPi. We hypothesized that PARP1 protein is regulated by its phosphorylation, and that phosphorylation status of PARP1 and the expression of the corresponding kinases that phosphorylate PARP1 will serve as appropriate biomarkers for combinational treatment. Multiple kinases can phosphorylate the same substrates, resulting in signal crosstalk. Also, TNBC is a heterogeneous disease, and the distinct kinases play an important role in different TNBC. Therefore, we also hypothesize that similar to c-Met, other protein kinases also have functions to regulate PARP1 activity through phosphorylation in TNBC. Potential molecules we will study are EGFR, which also directly interacts with PARP1 and phosphorylate it. We will investigate the role of these kinases in PARP1 regulation and PARPi resistance. Thus, we propose the following three aims; Aim 1. To systematically validate the significance of c-Met–mediated phosphorylation in PARPi resistance in mouse models and TNBC patient samples; Aim 2. To determine the role of EGFR-mediated PARP phosphorylation in PARPi resistance in TNBC; Aim 3. To determine the role of c-Met and EGFR interplay in PARPi resistance in TNBC. If our proposal is successful, several phosphorylation sites in PARP1 can be used as biomarkers to guide the combinational treatment of PARPi and correlated kinase inhibitors. We will particularly focus on c-Met and EGFR because inhibitors of these kinases are currently used in the clinic or in clinical trials, allowing for faster progression of our biomarker-guided rationale combination therapy into clinical trials.