Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Rong Wang,Tomoyoshi Yamano,Tadaaki Yamada,Akihiro Nishiyama,Sachiko Arai,Hisanori Uehara,Rikinari Hanayama,Hirokazu Taniguchi,Azusa Tanimoto,Takeshi Suzuki,Xujun Han,Akihiro Yoshimura,Kyoichi Kaira,Yoshihiko Taniguchi,Isao Matsumoto,Minoru Terashima,Koshiro Ohtsubo,Kunio Matsumoto,Shinji Takeuchi,Koji Fukuda,Shinji Atagi,K Takayama ,Akihiko Ishimura,Wei Wang,Kaname Yamashita,Kenji Kita,Seiji Yano

doi:10.1038/s41467-020-18442-4

Abstract

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC.

Highlights

2,14 ✉, Drug tolerance is the basis for acquired resistance to epidermal growth factor receptortyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear
We reported that in AXL-high-expressing EGFRmutated non-small cell lung cancer (NSCLC), a small population of tumor cells emerged tolerant to osimertinib as persisters by restoring the survival signal from AXL associated with EGFR and HER3, and the combined treatment with osimertinib and an AXL inhibitor prevented the development of acquired resistance to osimertinib[12]
While osimertinib inhibited the viability of all EGFR-mutated NSCLC cell lines tested in a dose-dependent manner, the IC50 values were lower in AXL-low-expressing tumor cell lines compared to the AXL-highexpressing tumor cell lines

Summary

Introduction

2,14 ✉, Drug tolerance is the basis for acquired resistance to epidermal growth factor receptortyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC. We reported that in AXL-high-expressing EGFRmutated NSCLC, a small population of tumor cells emerged tolerant to osimertinib as persisters by restoring the survival signal from AXL associated with EGFR and HER3, and the combined treatment with osimertinib and an AXL inhibitor prevented the development of acquired resistance to osimertinib[12]. The transient combination of the IGF-1R inhibitor with continuous osimertinib eradicated the tumor cells and prevented the regrowth in CDX and PDX models of AXLlow-expressing EGFR-mutated NSCLC

Methods

Results

Conclusion