biostudies-literatureUnknown33(4)Inano STargeted protein degradation is a promising strategy for addressing oncogenic drivers that are difficult to inhibit with small molecules, such as KRAS. While bioPROTACs expand the range of targetable proteins, their clinical translation is limited by inefficient delivery. To overcome this barrier, we engineered a chimeric protein, termed DEG-KRAS, which consists of a KRAS-binding domain derived from CRAF (RBD/CRD), an E3 adaptor (WSB1), and an optional trafficking module. DEG-KRAS induced degradation of active KRAS and suppressed proliferation in pancreatic cancer cell lines by reducing phospho-ERK levels. Notably, DEG-KRAS expression in mesenchymal stem cells (MSCs) exerted a bystander effect, leading to KRAS degradation and growth inhibition in co-cultured cancer cells. Specificity was cMolecular therapy. Oncology201077https://www.ebi.ac.uk/biostudies/studies/S-EPMC12663003biostudies-literatureTargeted degradation of KRAS and induction of bystander effects by a modular bioPROTAC.PMC12663003Nakajima TInano STakaori-Kondo AfalseTargeted degradation of KRAS and induction of bystander effects by a modular bioPROTAC.Targeted protein degradation is a promising strategy for addressing oncogenic drivers that are difficult to inhibit with small molecules, such as KRAS. While bioPROTACs expand the range of targetable proteins, their clinical translation is limited by inefficient delivery. To overcome this barrier, we engineered a chimeric protein, termed DEG-KRAS, which consists of a KRAS-binding domain derived from CRAF (RBD/CRD), an E3 adaptor (WSB1), and an optional trafficking module. DEG-KRAS induced degradation of active KRAS and suppressed proliferation in pancreatic cancer cell lines by reducing phospho-ERK levels. Notably, DEG-KRAS expression in mesenchymal stem cells (MSCs) exerted a bystander effect, leading to KRAS degradation and growth inhibition in co-cultured cancer cells. Specificity was c2025-01-01T00:00:00Z2025 Dec2026-06-06T07:17:18.98Z2026-06-06T03:07:09.231ZS-EPMC126630034132219510.1016/j.omton.2025.201077