Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges for targeted clinical interventions due to prevalent KRAS mutations, rendering PDAC resistant to RAF and MEK inhibitors (RAFi and MEKi). In addition, responses to targeted therapies vary between patients. Here, we explored the differential sensitivities of PDAC cell lines to RAFi and MEKi and developed an isogenic pair comprising the most sensitive and resistant PDAC cells. To simulate patient- or tumor-specific variations, we constructed cell-line-specific mechanistic models based on protein expression profiling and differential properties of KRAS mutants. These models predicted synergy between two RAFi with different conformation specificity (type I½ and type II RAFi) in inhibiting phospho-ERK (ppERK) and reducing PDAC cell viability. This synergy was experimentally validated across all four studied PDAC cell lines. Our findings underscore the need for combination approaches to inhibit the ERK pathway in PDAC.

Systems Biology Ireland University College Dublin Dublin Ireland

Systems Biology Ireland University College Dublin Dublin Ireland; Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin Ireland; School of Medicine and Medical Science University College Dublin Dublin Ireland

Systems Biology Ireland University College Dublin Dublin Ireland; Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin Ireland; School of Medicine and Medical Science University College Dublin Dublin Ireland; Department of Pharmacology Yale University School of Medicine New Haven CT USA

Systems Biology Ireland University College Dublin Dublin Ireland; Department of Histology and Embryology Faculty of Medicine and Dentistry Palacky University 779 00 Olomouc Czech Republic

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