Therapeutic Targeting of Epithelial Mesenchymal Cellular Plasticity in Pancreatic Cancer

Abstract

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) cells exist on a spectrum of epithelial (E) and quasimesenchymal (QM) transcriptional states with differences in sensitivity to FOLFIRINOX (FFX). GSK-3b is a key regulator PDAC cell epithelial-to-mesenchymal transition (EMT). Methods: In vitro analysis of PDAC cell lines combined with multi-omic analysis of data from GSK-3b inhibitor trial (NCT05077800) to evaluate treatment effects on EMT. Results: GSK-3b inhibition with elraglusib (ELRA) drives QM PDAC cells towards 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 (DEGs) in PDAC cell lines with tumors from PDAC patients treated in a safety cohort combining FFX, ELRA and losartan (LOS) demonstrated 97 overlapping DEGs with concordant directional changes. ELRA treatment consistently suppressed EMT pathway expression. Synergy of ELRA with cytotoxic doses of FFX in 3-D culture was observed only in QM PDAC lines. The FFX/ELRA combination demonstrated initial evidence of clinical benefit with 3 of 6 patients experiencing partial response (PR) for a duration of at least 20 months. Interestingly, PRs were observed in patients with tumors demonstrating baseline high proportional QM cells that transitioned to E predominant tumors with ELRA treatment. Lastly, the influx of M1 tumor associated macrophage (TAM), CD4/CD8 lymphocytes and NK cells was observed with ELRA clinical response using a combination of GeoMx, snRNA-seq and ferumoxytol-MRI. Conclusion: GSK-3b blockade synergizes with FFX by modulating PDAC plasticity while promoting the development of a tumor suppressive immune microenvironment.

Affiliated Institutions

• Massachusetts General Hospital US
• Beaumont Hospital IE
• Mass General Brigham US
• University of Pennsylvania US
• Harvard University Press US

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