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

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

doi:10.3390/cancers12020339

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.

Highlights

Over half a million new cases are diagnosed each year with head and neck cancer (HNC), makingHNC the seventh most common form of malignancy worldwide [1]
By comparing the response of patient-derived xenografts (PDXs) to cetuximab in vivo, we demonstrated that progression to cetuximab is associated with increased TGF-beta signaling by cancer-associated fibroblasts (CAFs)
S1A) indicate that all five PDXs responded to cetuximab

Summary

Introduction

Over half a million new cases are diagnosed each year with head and neck cancer (HNC), makingHNC the seventh most common form of malignancy worldwide [1]. Cancers 2020, 12, 339 in the care of patients with advanced or metastatic HNC [2,3,4,5]. Cetuximab is a monoclonal antibody designed to block ligand binding to the epidermal growth factor receptor (EGFR) ([6] and reviewed in [7]). EGFR is a transmembrane protein that, upon ligand binding, stimulates its intracellular tyrosine kinase activity that subsequently activates the mitogen-activated protein kinase (MAPK) pathway [8]. In HNC, EGFR is a key receptor that is known to be involved in tumor progression and metastasis and its expression associated with poor prognosis [9,10,11]. Despite the pivotal role of EGFR in HNC, blocking EGFR using cetuximab showed an overall minimal effect, and only a small fraction of HNC patients benefit from such treatment. The majority of patients who initially responded will develop resistance to cetuximab and experience disease relapse [5,12]

Methods

Results

Conclusion