Rac/Cdc42 inhibitors target pancreatic cancer cells and macrophages in the tumor microenvironment.

Authors

Anamaris Torres-Sanchez, Stephanie Dorta-Estremera, Victor P Carlo, Suranganie Dharmawardhane

Published in

Cancer treatment and research communications. Volume 48. Pages 101335. Jul 28, 2026. Epub Jul 28, 2026.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest forms of cancer, with a distinct extracellular matrix and immunosuppressive tumor microenvironment. Therefore, there is a critical need for therapies that simultaneously target metastatic cancer cells and immunosuppressive cells such as tumor associated macrophages (TAMS) that promote pancreatic cancer progression. Ras-activated homologous GTPases Rac and Cdc42 are ideal targets for pancreatic cancer therapy because they regulate cell migration/invasion, cell polarity/morphology, and cell viability/survival in cancer cells and immune cells, mainly through activation of their common downstream effector p21-activated kinase (PAK) via autophosphorylation. Rac, Cdc42, and PAK are poor prognostic factors in PDAC. Accordingly, we found phospho-PAK levels to be elevated in invasive PDAC from Puerto Rican patient tissue. The potential of the dual Rac/Cdc42 inhibitors MBQ-167 and MBQ-168 were tested in human and mouse PDAC cells or macrophages by pulldown assays for Rac and Cdc42 activation, MTT assays for cell viability, wound-healing assays for cell migration, phagocytosis, as well as co-culture assays with PDAC cells and macrophages. Results show that Rac/Cdc42 inhibitors significantly reduce active Rac and Cdc42 in pancreatic and macrophage cells. Both MBQ-167 and MBQ-168 reduced pancreatic cancer cell viability with higher efficacy than macrophage viability, and inhibited morphology and migration of both cell types. In Transwell co-culture, MBQ-167 and MBQ 168 decreased pancreatic cancer cell migration and reduced inflammatory mediators such as Interleukin-6 (IL-6), Chinase-3-like protein 1 (CHI3L1) and S100A8/A9 (calprotectin). Therefore, MBQ-167 and MBQ-168 are potential PDAC therapeutics by targeting both pancreatic cancer cells and macrophages in the TME.

PMID:
42520352
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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