Overcoming resistance of targeted EGFR monotherapy by inhibition of STAT3 escape pathway in soft tissue sarcoma.

Xiaochun Wang,Philip J Crowe,Jia-Lin Yang,Mark Yang,Nikolajs Zeps,Kerryn Garrett,David Goldstein

doi:10.18632/oncotarget.7452

Xiaochun Wang, Philip J Crowe + Show 5 more

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https://doi.org/10.18632/oncotarget.7452

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Journal: Oncotarget	Publication Date: Feb 17, 2016
Citations: 62	License type: cc-by

Affiliation: UNSW Sydney, University of Western Australia

Abstract

Although epidermal growth factor receptor (EGFR) is often over-expressed in soft tissue sarcoma (STS), a phase II trial using an EGFR inhibitor gefitinib showed a low response rate. This study identified a new secondary resistance mechanism of gefitinib in STS, and developed new strategies to improve the effectiveness of EGFR inhibition particularly by blocking the STAT3 pathway.We demonstrated that seven STS cell lines of diverse histological origin showed resistance to gefitinib despite blockade of phosphorylated EGFR (pEGFR) and downstream signal transducers (pAKT and pERK) in PI3K/AKT and RAS/ERK pathways. Gefitinib exposure was not associated with decrease in the ratio of pSTAT3/pSTAT1. The relative STAT3 abundance and activation may be responsible for the drug resistance. We therefore hypothesized that the addition of a STAT3 inhibitor could overcome the STAT3 escape pathway.We found that the addition of STAT3 inhibitor S3I-201 to gefitinib achieved synergistic anti-proliferative and pro-apoptotic effects in all three STS cell lines examined. This was confirmed in a fibrosarcoma xenografted mouse model, where the tumours from the combination group (418mm3) were significantly smaller than those from untreated (1032mm3) or single drug (912 and 798mm3) groups.Our findings may have clinical implications for optimising EGFR-targeted therapy in STS.

Highlights

Soft tissue sarcoma (STS) is a malignancy that arises from transformed cells of mesenchymal origin
We examined the expression of epidermal growth factor receptor (EGFR) relevant downstream signal transducers in these cell lines
To identify the potential escape pathways, we examined the impact of EGFR inhibition on the activity of two downstream pathways - PI3K/AKT and RAS/RAF/ ERK, using the soft tissue sarcoma (STS) cell lines with wild-type EGFR tyrosine kinase (TK), KRAS and BRAF genes (778, 449B and HT1080), so as to rule out any interference from gene mutation and using EGF to maximize downstream expression (Figure 2B and 2C, Supplementary Figure S2A)

Summary

Introduction

Soft tissue sarcoma (STS) is a malignancy that arises from transformed cells of mesenchymal origin. Current treatment for STS relies upon aggressive surgery, often in combination with radiotherapy and chemotherapy. Our current drug therapies have suboptimal outcomes and new treatments are needed. Epidermal growth factor receptor (EGFR) is activated following ligand binding to its extracellular domain This leads to phosphorylation of critical tyrosine residues which activates signalling cascades and induces gene transcription [3]. These include the RAS/ RAF/MAPK (mitogen activated protein kinase)/ERK (extracellular signal-regulated kinase (ERK, MAPK1), the PI3K (phosphatidylinositol 3-kinase, PIK3CA)/ AKT (Protein kinase B)/mTOR (mammalian target of rapamycin) and the JAK (Janus kinase)/STAT (signal transducers and activators of transcription) pathways. The activation of these pathways stimulates cellular www.impactjournals.com/oncotarget

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