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

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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.