Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors
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...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
|
| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225001026 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832540386982100992 |
|---|---|
| author | Giorgia Anastasio Michela Felaco Alessia Lamolinara Francesco del Pizzo Elisa Cacciagrano Carla Mottini Margherita Mutarelli Francesca Di Modugno Manuela Iezzi Luca Cardone |
| author_facet | Giorgia Anastasio Michela Felaco Alessia Lamolinara Francesco del Pizzo Elisa Cacciagrano Carla Mottini Margherita Mutarelli Francesca Di Modugno Manuela Iezzi Luca Cardone |
| author_sort | Giorgia Anastasio |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4ed6d7b6df6e48d8acc829dd42f9f59c |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-4ed6d7b6df6e48d8acc829dd42f9f59c2025-02-05T04:32:31ZengElsevieriScience2589-00422025-02-01282111842Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumorsGiorgia Anastasio0Michela Felaco1Alessia Lamolinara2Francesco del Pizzo3Elisa Cacciagrano4Carla Mottini5Margherita Mutarelli6Francesca Di Modugno7Manuela Iezzi8Luca Cardone9Institute of Biochemistry and Cellular Biology, National Research Council, Monterotondo-Scalo, 00015 Rome, ItalyInstitute 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, ItalyCenter for Advanced Studies and Technology, 66100 Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyCenter for Advanced Studies and Technology, 66100 Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyCenter for Advanced Studies and Technology, 66100 Chieti, Italy; Department of Neurosciences, Imaging and Clinical Sciences, G. d’Annunzio University of Chieti-Pescara, 66100 Chieti, ItalyUOSD SAFU Translational Research Area, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyInstitute of Applied Sciences and Intelligent Systems, National Research Council, 80078 Naples, ItalyUnit of Tumor Immunology and Immunotherapy, IRCCS Regina Elena National Cancer Institute, 00144 Rome, ItalyCenter 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 authorInstitute 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 authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004225001026PharmacologyCancer |
| spellingShingle | Giorgia Anastasio Michela Felaco Alessia Lamolinara Francesco del Pizzo Elisa Cacciagrano Carla Mottini Margherita Mutarelli Francesca Di Modugno Manuela Iezzi Luca Cardone Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors iScience Pharmacology Cancer |
| title | Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors |
| title_full | Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors |
| title_fullStr | Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors |
| title_full_unstemmed | Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors |
| title_short | Enhancing PDAC therapy: Decitabine-olaparib synergy targets KRAS-dependent tumors |
| title_sort | enhancing pdac therapy decitabine olaparib synergy targets kras dependent tumors |
| topic | Pharmacology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225001026 |
| work_keys_str_mv | AT giorgiaanastasio enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT michelafelaco enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT alessialamolinara enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT francescodelpizzo enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT elisacacciagrano enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT carlamottini enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT margheritamutarelli enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT francescadimodugno enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT manuelaiezzi enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors AT lucacardone enhancingpdactherapydecitabineolaparibsynergytargetskrasdependenttumors |