Inhibition of collagen receptor discoidin domain receptor-1 (DDR1) tyrosine kinase enhances cytotoxicity of anti-mesothelin immunotoxin for cancer therapy

Wednesday, September 24, 2014 — Poster Session IV
10:00 a.m. –12:00 p.m.	FAES Academic Center	NCI	CANCER-1

Authors

• F Ali-Rahmani
• D Fitzgerald
• S Martin
• P Patel
• C Thomas
• I Pastan

Abstract

Discoidin domain receptor 1 (DDR1) is an emerging anti-cancer target, a tyrosine kinase activated by collagen, most abundant in stroma. Collagen-mediated-induction of DDR1 facilitates cell adhesion, migration, and proliferation, can modulate tumor-stromal interaction and can affect tumor response to therapy. Mesothelin is a cell-surface tumor-associated antigen over-expressed in several human cancers including mesothelioma, ovarian, lung, breast, and pancreatic cancers with limited expression on normal cells. RG7787 is a clinically optimized recombinant immunotoxin (RIT) consists of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A in which immunogenic B-cell epitopes are silenced. We hypothesized that DDR1 regulates RIT activity and its inhibition might enhance the activity of RG7787. Knockdown of DDR1 by siRNA or its inhibition with a novel inhibitor, '7rh', synergistically enhanced cytotoxicity of RG7787 in several cancer cell lines. Stimulation of DDR1 activity by collagen treatment protected cancer cells from killing by RG7787. However, this collagen-mediated-resistance of cancer cells to RIT therapy can be overcome by addition of 7rh. In conclusion, our data suggest that the combination of '7rh' and RG7787 represents a novel therapeutic strategy to target mesothelin-expressing cancers. These data also provide insight into how tumor stroma might be protecting cancer cells from therapy.

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