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

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    20 Citations (Scopus)

    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 (CetuximabProg-PDX). However, in PDXs that were extremely sensitive to cetuximab (CetuximabSen-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 CetuximabProg-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 CetuximabProg-PDX. Altogether, our findings indicate that TGF-beta-activated CAFs play a role in limiting cetuximab efficacy in HNC.

    Original languageEnglish
    Article number339
    JournalCancers
    Volume12
    Issue number2
    DOIs
    Publication statusPublished - Feb 2020

    Keywords

    • Cancer-associated fibroblast
    • Cetuximab
    • Head and neck cancer
    • Therapy resistance
    • Tumor microenvironment

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