A small-molecule compound D6 overcomes EGFR-T790M-mediated resistance in non-small cell lung cancer

Xiaolong Tang,Guo Li,Baohua Liu,Dan-Ling Huang,Yong-Ming Yan,Shuping Zhang,Lizhi Cheng,Ji Li,Yong-Xian Cheng,Minxian Qian,Fengting Su,Zuojun Liu

doi:10.1038/s42003-021-02906-4

Abstract

Non-small cell lung cancer (NSCLC) is a deadly and highly prevalent malignancy. Targeting activated-EGFR mutations in NSCLC via EGFR tyrosine kinase inhibitor (EGFR-TKI) initially achieves a profound therapeutic response, but resistance frequently evolves, reducing treatment options. Here, we present a small-molecule compound D6 which selectively inhibits tumor cell growth and migration in NSCLC cells with EGFR-TKI-resistant T790M-EGFR-activated mutations (T790M-EGFR-AM), e.g., L858R/T790M, 19Del/T790M and L858R/T790M/C797S. D6 mimics a natural product isolated from the roots of Codonopsis pilosula and selectively competes with T790M-EGFR-AM to bind to HSP90, thus facilitating the ubiquitination dependent proteasomal degradation of T790M-EGFR-AM. By contrast, D6 has little impact on typical HSP90 chaperone activity, suggesting low systemic toxicity. Promisingly, D6 combined with erlotinib or osimertinib shows efficacy in overcoming the EGFR-TKIs-resistance in NSCLCs. Our study raises an alternative strategy to overcome T790M-mediated EGFR-TKI resistance in NSCLC via targeting the protein–protein interaction of HSP90 and T790M-EGFR by intervention with D6.

Highlights

Non-small cell lung cancer (NSCLC) is a deadly and highly prevalent malignancy
Since NCI-H1975 cells expressing EGF-TKIs-resistant L858R/T790MEGFR were more sensitive to D6, we investigated if D6 selectively targets the L858R/T790M-Epidermal growth factor receptor (EGFR) mutated NSCLCs
To confirm that D6 preferentially targets L858R/T790M-EGFR in NSCLC, we asked which architecture of EGFR is indispensable in response to D6, i.e., L858R, T790M alone or both; we investigated if the observed effects are cell-type specific

Summary

Introduction

Targeting activated-EGFR mutations in NSCLC via EGFR tyrosine kinase inhibitor (EGFR-TKI) initially achieves a profound therapeutic response, but resistance frequently evolves, reducing treatment options. We present a small-molecule compound D6 which selectively inhibits tumor cell growth and migration in NSCLC cells with EGFR-TKI-resistant T790MEGFR-activated mutations (T790M-EGFR-AM), e.g., L858R/T790M, 19Del/T790M and L858R/T790M/C797S. NSCLCs harboring EGFR-activated mutations are more sensitive to EGFR tyrosine kinase inhibitors (EGFR-TKIs). The first generation of TKIs (erlotinib and gefitinib) are widely applied for 19Del- or L858R-EGFR-positive patients[9]. To overcome the T790M-EGFR resistance, osimertinib, a representative third generation of EGFR-TKIs, which acts irreversibly and selectively for EGFR-activating mutations including T790M mutation, has been widely applied in clinic[15,16]. HSP90 belongs to the heat-shock protein family and assists protein folding or refolding[20] and oncogenic proteins levels, maturation, and continued dysregulated activity are regulated by HSP90 chaperone activity in many cancers[21]

Methods

Results

Conclusion