Therapeutic synergism of PARP and dipeptidyl pepti-dase-4 inhibition in triple-negative breast cancer

三阴性乳腺癌是所有乳腺癌亚型中预后最差的，到目前为止，经典化疗仍然是唯一的全身治疗选择。最近，聚(ADP-核糖)聚合酶1(PARPI)的抑制剂已被批准用于转移性乳腺癌患者和DNA修复基因BRCA1或BRCA2之一的突变。然而，许多患者对PARPI治疗没有反应，这引发了潜在的耐药机制和预测生物标志物的问题。在过去的几个月里，几个研究小组独立地证明了PARPI在肿瘤细胞中诱导某些趋化因子(CXCL9、CXCL10、CCL5)。这些趋化因子在化学上将抑制肿瘤的淋巴细胞吸引到肿瘤微环境中，从而诱导对肿瘤的免疫反应。在临床前模型中，PARPI治疗的成功甚至依赖于这种免疫激活，这一作用机制可能解释了PARPI效应，特别是在BRCA野生型肿瘤中。PARPI诱导的趋化因子与已知的被二肽基肽酶-4(DPP4)切割和失活的趋化因子完全相同。我们的初步结果显示，大约70%的TNBC表达DPP4，这种表达与显著降低的无进展和总生存期有关。因此，我们假设DPP4的过表达通过蛋白水解性趋化因子失活来削弱PARPI效应。由于DPP4抑制剂(如西格列汀)普遍可用且临床特征良好，这种打破PARPI耐药性的方法很容易在未来的临床试验中实施。为了检验这一假设，我们将检验在PARPI刺激下TNBC细胞分泌哪些趋化因子，以及哪些趋化因子负责淋巴细胞趋化。在TNBC的同基因小鼠模型中，我们将研究PARPI治疗的成功在多大程度上取决于这种趋化因子的释放，以及BRCA突变和非突变肿瘤在这方面是否存在差异。接下来，我们想要阐明DPP4的过度表达或DPP4的抑制对PARPI反应有什么影响。最后，在一项探索性临床研究中，我们将检查这种趋化因子诱导是否也出现在接受PARPI治疗的TNBC患者的血液中，以及它是否可以预测治疗反应。结果旨在将DPP4过度表达定义为一种新的PARPI耐药机制，并通过协同抑制DPP4来改进PARPI治疗。

Triple-negative breast cancer has the worst prognosis of all breast cancer subtypes, and classic chemotherapies remained the only systemic therapy option until now. Most recently, inhibitors of the poly(ADP-ribose) polymerase 1 (PARPi) have been approved for patients with metastatic breast cancer and a mutation in one of the DNA repair genes BRCA1 or BRCA2. However, many patients do not respond to PARPi therapy which raises the question of underlying resistance mechanisms and predictive biomarkers.During the past months several research groups have independently shown that PARPi induce certain chemokines (CXCL9, CXCL10, CCL5) in tumor cells. These chemokines chemotactically attract tumor-suppressive lymphocytes to the tumor microenvironment, thereby inducing an immune reaction against the tumor. In preclinical models the success of a PARPi therapy was even dependent on this immune activation, and this mechanism of action might explain the PARPi effects especially in BRCA wild-type tumors. The chemokines induced by PARPi are exactly the same known to be cleaved and inactivated by the protease dipeptidyl peptidase-4 (DPP4). Our preliminary results show that about 70% of all TNBC express DPP4 and that this expression is associated with a significantly reduced progression-free and overall survival. We therefore postulate that a DPP4 overexpression impairs PARPi effect by proteolytic chemokine inactivation. As DPP4 inhibitors (e.g. sitagliptin) are generically available and clinically well characterized, this approach of breaking PARPi resistance would be easy to implement into future clinical trials.To test this hypothesis we will examine which chemokines are secreted from TNBC cells upon PARPi stimulation and which of them are responsible for lymphocytic chemotaxis. In syngeneic mouse models of TNBC we will then study to what extend the success of a PARPi therapy depends on this chemokine release and if there is a difference between BRCA mutated and non-mutated tumors in this regard. Next, we want to clarify what impact DPP4 overexpression or DPP4 inhibition has on PARPi reponse. Finally, in an exploratory clinical study we will examine if this chemokine induction is also seen in the blood of TNBC patients under PARPi therapy and if it predicts therapy response.The results are intended to define DPP4 overexpression as a new resistance mechanism against PARPi and to improve PARPi therapy by synergistically inhibiting DPP4.