TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer

Ksenia M Yegodayev; Ofra Novoplansky; Artemiy Golden; Manu Prasad; Liron Levin; Sankar Jagadeeshan; Jonathan Zorea; Orr Dimitstein; Ben-Zion Joshua; Limor Cohen; Ekaterina Khrameeva; Moshe Elkabets

doi:10.3390/cancers12020339

TGF-Beta-Activated Cancer-Associated Fibroblasts Limit Cetuximab Efficacy in Preclinical Models of Head and Neck Cancer

Cancers (Basel). 2020 Feb 3;12(2):339. doi: 10.3390/cancers12020339.

Authors

Ksenia M Yegodayev^{1

2}, Ofra Novoplansky^{1

2}, Artemiy Golden³, Manu Prasad^{1

2}, Liron Levin⁴, Sankar Jagadeeshan^{1

2}, Jonathan Zorea^{1

2}, Orr Dimitstein^{2

5}, Ben-Zion Joshua^{2

5}, Limor Cohen^{1

2}, Ekaterina Khrameeva³, Moshe Elkabets^{1

2}

Affiliations

¹ The Shraga Segal Department of Microbiology, Immunology, and Genetics, 84105 Beer-Sheva, Israel.
² Faculty of Health Sciences, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
³ Center of Life Sciences, Skolkovo Institute of Science and Technology, 121205 Moscow, Russia.
⁴ Bioinformatics Core Facility, National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, 84105 Beer-Sheva, Israel.
⁵ Department of Otolaryngology-Head & Neck Surgery, Soroka University Medical Center, 84105 Beer-Sheva, Israel.

Abstract

Most head and neck cancer (HNC) patients are resistant to cetuximab, an antibody against the epidermal growth factor receptor. Such therapy resistance is known to be mediated, in part, by stromal cells surrounding the tumor cells; however, the mechanisms underlying such a resistance phenotype remain unclear. To identify the mechanisms of cetuximab resistance in an unbiased manner, RNA-sequencing (RNA-seq) of HNC patient-derived xenografts (PDXs) was performed. Comparing the gene expression of HNC-PDXs before and after treatment with cetuximab indicated that the transforming growth factor-beta (TGF-beta) signaling pathway was upregulated in the stromal cells of PDXs that progressed on cetuximab treatment (Cetuximab^Prog-PDX). However, in PDXs that were extremely sensitive to cetuximab (Cetuximab^Sen-PDX), the TGF-beta pathway was downregulated in the stromal compartment. Histopathological analysis of PDXs showed that TGF-beta-activation was detected in cancer-associated fibroblasts (CAFs) of Cetuximab^Prog-PDX. These TGF-beta-activated CAFs were sufficient to limit cetuximab efficacy in vitro and in vivo. Moreover, blocking the TGF-beta pathway using the SMAD3 inhibitor, SIS3, enhanced cetuximab efficacy and prevented the progression of Cetuximab^Prog-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.

Keywords: Cetuximab; cancer-associated fibroblast; head and neck cancer; therapy resistance; tumor microenvironment.

Abstract

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