{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE314nnn/GSE314343/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE314343"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Interference with PADI1 and PADI3 re-sensitizes KRAS-Mutant PDAC and CRC to KRAS ON/OFF Inhibitors by Promoting Non-lytic Apoptosis","description":"The development of KRAS-ON and KRAS-OFF inhibitors enabled the selective targeting of KRAS-addicted tumors, offering new therapeutic options for malignancies refractory to conventional treatments, such as metastatic colorectal cancer (CRC), lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC). However, intrinsic or acquired resistance significantly limited their clinical potential. In this study, we demonstrated that in CRC, LUAD, and PDAC patients harboring activating KRAS mutations the expression of peptidylarginine deiminases PADI1 and, most notably, PADI3 represented negative prognostic markers. KRAS-driven metabolic rewiring, hypoxia, and acidosis sustained PADI1 and PADI3 expression through activation of an upstream enhancer of PADI1. KRAS inhibition resulted in loss of PADI1 and PADI3 expression, whereas cellular models resistant to enforced KRAS degradation maintained basal expression levels of PADI1 and 3. Pharmacological inhibition of PADIs using BBCl amidine or two selective PADI3 inhibitors synergized with KRAS-ON and KRAS-OFF inhibitors in two- and three-dimensional CRC and PDAC models, as well as in a PDAC murine xenograft. Transcriptomic and proteomic analyses, together with CRISPR/Cas9 loss-of-function screening, revealed that co-treatment activated a non-lytic apoptotic mechanism characterized by sustained membrane integrity, absence of Damage-Associated Molecular Pattern (DAMP) release, and lack of nuclear expulsion-like phenomena. Collectively, our findings uncovered a novel therapeutic strategy to overcome resistance to KRAS inhibitors by exploiting a class of compounds that remained largely underexplored in oncology.","dates":{"publication":"2026/08/21"},"accession":"GSE314343","cross_references":{"GSM":["GSM9393919","GSM9393909","GSM9393917","GSM9393928","GSM9393929","GSM9393918","GSM9393915","GSM9393926","GSM9393927","GSM9393916","GSM9393924","GSM9393913","GSM9393914","GSM9393925","GSM9393922","GSM9393911","GSM9393912","GSM9393923","GSM9393920","GSM9393931","GSM9393910","GSM9393932","GSM9393921","GSM9393930"],"GPL":["24676"],"GSE":["314343"],"taxon":["Homo sapiens"]}}