IL-26 mediates epidermal growth factor receptor-tyrosine kinase inhibitor resistance through endoplasmic reticulum stress signaling pathway in triple-negative breast cancer cells

Takumi Itoh,Chikao Morimoto,Haruna Otsuka,Ko Okumura,Ryo Hatano,Dan Song,Thomas M Aune,Noriaki Iwao,Nam H Dang,Yutaro Kaneko,Yoshiya Horimoto,Yuki Shirakawa,Taketo Yamada,Shuji Mastuoka,Kei Ohnuma

doi:10.1038/s41419-021-03787-5

Abstract

Triple-negative breast cancer (TNBC) has a poor prognosis compared to other breast cancer subtypes. Although epidermal growth factor receptor (EGFR) is overexpressed in TNBC, clinical trials with EGFR inhibitors including tyrosine kinase inhibitors (EGFR-TKI) in TNBC have heretofore been unsuccessful. To develop effective EGFR-targeted therapy for TNBC, the precise mechanisms of EGFR-TKI resistance in TNBC need to be elucidated. In this study, to understand the molecular mechanisms involved in the differences in EGFR-TKI efficacy on TNBC between human and mouse, we focused on the effect of IL-26, which is absent in mice. In vitro analysis showed that IL-26 activated AKT and JNK signaling of bypass pathway of EGFR-TKI in both murine and human TNBC cells. We next investigated the mechanisms involved in IL-26-mediated EGFR-TKI resistance in TNBC. We identified EphA3 as a novel functional receptor for IL-26 in TNBC. IL-26 induced dephosphorylation and downmodulation of EphA3 in TNBC, which resulted in increased phosphorylation of AKT and JNK against EGFR-TKI-induced endoplasmic reticulum (ER) stress, leading to tumor growth. Meanwhile, the blockade of IL-26 overcame EGFR-TKI resistance in TNBC. Since the gene encoding IL-26 is absent in mice, we utilized human IL-26 transgenic (hIL-26Tg) mice as a tumor-bearing murine model to characterize the role of IL-26 in the differential effect of EGFR-TKI in human and mice and to confirm our in vitro findings. Our findings indicate that IL-26 activates the bypass pathway of EGFR-TKI, while blockade of IL-26 overcomes EGFR-TKI resistance in TNBC via enhancement of ER stress signaling. Our work provides novel insights into the mechanisms of EGFR-TKI resistance in TNBC via interaction of IL-26 with its newly identified receptor EphA3, while also suggesting IL-26 as a possible therapeutic target in TNBC.

Highlights

Accounting for 15–20% of breast cancer, triple-negative breast cancer (TNBC) subtype lacks estrogen receptor, progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) expression and has a poor prognosis[1,2,3,4]
IL-26-positive tumor-infiltrating lymphocytes (TILs) were observed in all subtypes, the mean percentage of IL-26-positive TILs in TNBC and HER2 type was significantly higher than luminal tumors (Fig. 1B)
Exogenous IL-26 activates bypass pathway of Epidermal growth factor receptor (EGFR)-TKI in mouse and human TNBC We evaluated the effects of exogenous IL-26 in combination with EGFR-TKI treatment on murine TNBC

Summary

Introduction

Accounting for 15–20% of breast cancer, triple-negative breast cancer (TNBC) subtype lacks estrogen receptor, progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) expression and has a poor prognosis[1,2,3,4]. The molecular mechanisms involved in the differences in efficacy of EGFR-TKI on TNBC between human and mouse model should be elucidated to overcome. We previously reported that IL-26 secreted by CD4 + T cells activates fibroblasts for collagen production via its functional receptor IL-20RA/IL-10RB, and that IL-26 has an important role in lung fibrosis of chronic graft-versushost disease[13]. The lack of IL-26 in appropriate murine models has impeded research to understand cross-species differences in EGFR-TKI susceptibility or resistance in TNBC. To address this important issue, we expand on our previous findings and define the molecular mechanisms involved in IL-26-mediated

Methods

Results

Conclusion