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，其经常复发， 导致比激素受体阳性亚型患者更差的结果。PARP目前是 已经开发了用于TNBC的最有前途的药物靶标和多种PARP抑制剂（PARPi）， 在临床试验中测试。虽然PARPi在携带BRCA突变的患者中显示出更高的应答率， 仍然有很高比例的携带BRCA突变的患者对PARPi没有反应。因此，在本发明中， 制定战略，使PARPi治疗更有效，并确定生物标志物分层 病人是关键。我们最近在Nature Medicine（2016）上发表的文章表明， 氧物种，c-Met与PARP 1在Y 907处相互作用并磷酸化PARP 1。此外，我们证明了 c-Met介导的磷酸化对于PARPi抗性是关键的，并且c-Met抑制剂敏化 TNBC细胞与PARPi。我们研究的长期目标是开发有效的治疗方法， TNBC战略。为此，我们将寻求新的生物标志物和治疗策略，以改善 PARPi的功效我们假设PARP 1蛋白受其磷酸化调节， PARP 1的磷酸化状态和相应激酶的表达， 磷酸化PARP 1将用作组合治疗的适当生物标志物。多 激酶可以磷酸化相同的底物，导致信号串扰。此外，TNBC是一个 这些激酶在不同的TNBC中起重要作用，并且不同的激酶在不同的TNBC中起重要作用。因此，我们认为， 我们还假设，与c-Met类似，其他蛋白激酶也具有调节PARP 1的功能 通过磷酸化在TNBC中的活性。我们将研究的潜在分子是EGFR， 直接与PARP 1相互作用并使其磷酸化。我们将研究这些激酶在 PARP 1调节和PARPi抗性。因此，我们提出以下三个目标：目标1。到 系统地验证了c-Met介导的磷酸化在PARPi抗性中的意义， 小鼠模型和TNBC患者样品;目的2.为了确定EGFR介导的PARP的作用 TNBC中PARPi抗性的磷酸化; Aim 3.确定c-Met和EGFR的作用 在TNBC中PARPi抗性相互作用。如果我们的方案成功， PARP 1可用作生物标志物以指导PARPi的组合治疗和相关的免疫治疗。 激酶抑制剂。我们将特别关注c-Met和EGFR，因为这些激酶的抑制剂是 目前在临床或临床试验中使用，允许我们的生物标志物引导的更快进展 临床试验中的合理组合疗法。

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.