Institute of Biochemistry and Cellular Biology, National Research Council, Monterotondo-Scalo, 00015 Rome, Italy
Michela Felaco
Institute of Biochemistry and Cellular Biology, National Research Council, Monterotondo-Scalo, 00015 Rome, Italy; Unit of Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
Alessia Lamolinara
Center for Advanced Studies and Technology, 66100 Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
Francesco del Pizzo
Center for Advanced Studies and Technology, 66100 Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
Elisa Cacciagrano
Center for Advanced Studies and Technology, 66100 Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy
Carla Mottini
UOSD SAFU Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
Margherita Mutarelli
Institute of Applied Sciences and Intelligent Systems, National Research Council, 80078 Naples, Italy
Francesca Di Modugno
Unit of Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy
Manuela Iezzi
Center for Advanced Studies and Technology, 66100 Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, Italy; Corresponding author
Luca Cardone
Institute of Biochemistry and Cellular Biology, National Research Council, Monterotondo-Scalo, 00015 Rome, Italy; Unit of Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, 00144 Rome, Italy; Corresponding author
Summary: Pancreatic ductal adenocarcinoma (PDAC) shows limited response to chemotherapy, partly due to the absence of effective biomarkers for personalized treatment. Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 90% of PDAC cases, and tumors dependent on KRAS (dKRAS) can be identified using gene expression signature scores. Previous research indicates that dKRAS-PDAC cells are sensitive to decitabine (DEC), an FDA-approved drug for hematological cancers, though its use in solid tumors is limited by side effects. We discovered that low-dose DEC combined with the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (OLA) enhances antitumor activity in dKRAS-PDAC. DEC induces DNA damage and activates the ataxia telangiectasia (ATR)/ataxia telangiectasia mutated (ATM)-mediated DNA damage response (DDR), with PARP1-mediated repair playing a key role. Inhibiting PARP with OLA further improves efficacy, even in BRCA1/2-wild-type and homologous recombination (HR)-proficient tumors but not in KRAS-independent tumors. The combination was especially effective in dKRAS-PDAC with a BRCA2 mutation, preventing metastasis growth. Our results support the clinical evaluation of DEC+OLA in PDAC.
