British journal of cancer · 2024
ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment.
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Bruciamacchie Marine, Garambois Véronique, Vie Nadia, Bessede Thomas, Michaud Henri-Alexandre, Chepeaux Laure-Agnès, Gros Laurent, Bonnefoy Nathalie, Robin Mathilde, Brager Dorian, Bigot Kevin, Evrard Alexandre, Pourquier Philippe, Colinge Jacques, Mathonnet Muriel, Belhabib Ismahane, Jean Christine, Bousquet Corinne, Colombo Pierre-Emmanuel, Jarlier Marta, Tosi Diégo, Gongora Céline, Larbouret Christel
Аннотация
BACKGROUND: In pancreatic ductal adenocarcinoma (PDAC), the dense stroma rich in cancer-associated fibroblasts (CAFs) and the immunosuppressive microenvironment confer resistance to treatments. To overcome such resistance, we tested the combination of FOLFIRINOX (DNA damage-inducing chemotherapy drugs) with VE-822 (an ataxia-telangiectasia and RAD3-related inhibitor that targets DNA damage repair).
METHODS: PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models.
RESULTS: The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction.
CONCLUSION: The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.
METHODS: PDAC spheroid models and organoids were used to assess the combination effects. Tumour growth and the immune and fibrotic microenvironment were evaluated by immunohistochemistry, single-cell analysis and spatial proteomics in patient-derived xenograft (PDX) and orthotopic immunocompetent KPC mouse models.
RESULTS: The FOLFIRINOX and VE-822 combination had a strong synergistic effect in several PDAC cell lines, whatever their BRCA1, BRCA2 and ATM mutation status and resistance to standard chemotherapy agents. This was associated with high DNA damage and inhibition of DNA repair signalling pathways, leading to increased apoptosis. In immunocompetent and PDX mouse models of PDAC, the combination inhibited tumour growth more effectively than FOLFIRINOX alone. This was associated with tumour microenvironment remodelling, particularly decreased proportion of fibroblast activated protein-positive CAFs and increased anti-tumorigenic immune cell infiltration and interaction.
CONCLUSION: The FOLFIRINOX and VE-822 combination is a promising strategy to improve FOLFIRINOX efficacy and overcome drug resistance in PDAC.
Предметные рубрики MeSH
Tumor MicroenvironmentAnimalsCarcinoma, Pancreatic DuctalOxaliplatinHumansMiceIrinotecanAntineoplastic Combined Chemotherapy ProtocolsAtaxia Telangiectasia Mutated ProteinsFluorouracilPancreatic NeoplasmsLeucovorinXenograft Model Antitumor AssaysCell Line, TumorDrug SynergismDNA DamageDNA RepairFemale