Abstract
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 confirmed using control constructs lacking each functional domain. Although the antiproliferative effect was modest compared to direct expression in cancer cells, the indirect impact highlights a non-cell-autonomous mechanism. While the precise mode of intercellular transfer remains to be elucidated, these findings suggest the involvement of extracellular vehicles or other secretory pathways. This strategy may offer a novel therapeutic avenue for targeting KRAS-driven tumors, particularly pancreatic adenocarcinoma.