Therapeutic Targeting of Epithelial-Mesenchymal Cellular Plasticity in Pancreatic Cancer.

[PURPOSE] Pancreatic ductal adenocarcinoma (PDAC) cells exist on a spectrum of epithelial (E) and quasi-mesenchymal (QM) transcriptional states, with differences in sensitivity to FOLFIRINOX (FFX). Glycogen synthase kinase 3β (GSK-3β) is a key regulator of PDAC cell epithelial-to-mesenchymal transition (EMT).

[PATIENTS AND METHODS] In vitro analysis of PDAC cell lines combined with multiomic analysis of data from a GSK-3β inhibitor trial (NCT05077800) was conducted to evaluate treatment effects on EMT.

[RESULTS] GSK-3β inhibition with elraglusib (ELRA) drives QM PDAC cells toward an E state, demarcated by decreased transcription of QM genes FN1 and TGFB1 and an induction of E genes KRT8 and CEACAM6. A comparison of differentially expressed genes (DEG) in PDAC cell lines with tumors from patients with PDAC treated in a safety cohort combining FFX, ELRA, and losartan demonstrated 97 overlapping DEGs with concordant directional changes. ELRA treatment consistently suppressed EMT pathway expression. The synergy of ELRA with cytotoxic doses of FFX in 3D culture was observed only in QM PDAC lines. The FFX/ELRA combination demonstrated initial evidence of clinical benefit, with three of six patients experiencing a partial response (PR) for a duration of at least 20 months. Interestingly, PRs were observed in patients with tumors demonstrating a baseline high proportion of QM cells that transitioned to E predominant tumors with ELRA treatment. Lastly, the influx of M1 tumor-associated macrophages, CD4/CD8 lymphocytes, and NK cells was observed with ELRA clinical response using a combination of GeoMx, snRNA-seq, and ferumoxytol-enhanced MRI.

[CONCLUSIONS] GSK-3β blockade synergizes with FFX by modulating PDAC plasticity while promoting the development of a tumor-suppressive immune microenvironment.