Résumé
Pancreatic Ductal Adenocarcinoma (PDAC) is an extremely aggressive disease.There is a clear need of new strategies and new researches to treat and diagnose these patients. Regarding treatments, surgery is possible in only 20% of cases, and the chemotherapeutic molecule Gemcitabine is unfortunately lacking a good response rate. Recently, a new polychemotherapy oxaliplatin-based (FOLFIRINOX), which is a combination of 4 drugs: oxaliplatin, irinotecan, fluorouracil and leucovorin, has been approved. It has showed a significant increase of the overall survival inpatients compared to gemcitabine, but associated with more toxicity and still limited efficiency. Most of the drugs induce their toxicity by provoking DNA damages and replication stress, leading to the activation of DNA repair pathways. In this context,our research project proposes to find a synergistic association of FOLFIRINOX with specific inhibitors of DNA damage repair -Ataxia Telangiectasia and Rad3 related inhibitor (ATRi)- to increase the efficiency of the chemotherapy while reducing itstoxicity. The resistance to chemotherapy can come from the stroma that represents up to 80% of the tumor mass. The impact of the chemotherapies on the microenvironment can be a key to increase the treatments efficiency. That’s why in this project, we studied co-culture models to look at the effect of this new polychemotherapy on tumor cells and its microenvironment, in particular Cancer-Associated Fibroblasts (CAFs). Viability matrix in 2D & 3D in vitro co-culture of tumor cells with primary CAFs were carried out. DNA damage and proteins from the DNA damage repair pathways were analysed after treatments. Cell death and autophagy pathways were studied. In vivo, immunodeficient mice xenografted with ATCC and Patient Derived Xenograft models were treated with FOLFIRINOX and ATRi to evaluate the effect on tumor progression. A synergistic effect of the association was demonstrated in vitro independently of the KRAS, ATM, TP53, BRCA1/2 mutation statuts in several pancreatic models (ATCC and derived from PDX) and in co-culture with CAFs. A higher apoptosis and DNA damages were observed in tumor cells treated with the associated drugs. These results were associated with a decrease of DNA damage repair pathways leading to more apoptosis compared to the chemotherapy alone and an inhibition of the autophagy flux. Also, a phenotypic change in the cells was found after treating with ATRi and with an increase of this particular phenotype when the chemotherapy was added. A protective effect of the CAFs on tumor cells was observed and CAF secretome was analysed. In vivo, the association inhibits significantly the tumor growth compared to each treatment alone and no toxicity was observed. Now, validation of this polychemotherapy in vivo using co-culture models in immunodeficient and immunocompetent mice are crucial to confirm the therapeutic potential of this new treatment for PDAC.
Citation Format: Marine Bruciamacchie, Nadia Vie, Véronique Garambois, Diego Tosi, Pierre-Emmanuel Colombo, Céline Gongora, Christel Larbouret. Effect of folfirinox with an ATR inhibitor on pancreatic tumor cells and its microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2589.