Aspirin sensitizes osimertinib-resistant NSCLC cells invitro and invivo via Bim-dependent apoptosis induction.

Rui Han,Caiyu Lin,Chong Zhang,Conghua Lu,Li Li,Yubo Wang,Shuai Hao,Yong He,Chen Hu

doi:10.1002/1878-0261.12682

Abstract

Osimertinib, a third‐generation irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI), provides marked clinical benefit for patients with EGFR‐activating mutations. Unfortunately, limited treatments exist for patients who acquire osimertinib resistance. We observed two ‘special’ patients who regained an antitumor response with osimertinib plus aspirin treatment. As previous data indicate that aspirin induces antiproliferative effects in tumor cells, we designed a preclinical study to explore whether aspirin combined with osimertinib could synergistically sensitize osimertinib‐resistant non‐small‐cell lung cancer (NSCLC) cells. The effects of combined treatment with osimertinib and aspirin on osimertinib‐resistant NSCLC cell lines were examined in vitro and in vivo. The combination of osimertinib and aspirin induced strong antiproliferative and proapoptotic effects in osimertinib‐resistant NSCLC cells through inhibition of Akt/FoxO3a signaling component phosphorylation and increased Bim expression. Furthermore, Bim knockdown by siRNA significantly attenuated osimertinib resensitization by aspirin. In vivo, combination of aspirin and osimertinib significantly decreased tumor growth of PC‐9GROR cell xenografts. Data of patients with NSCLC who received osimertinib treatment at Daping Hospital between January 2015 and January 2019 were reviewed retrospectively. According to clinical data for 45 patients with NSCLC, retrospective analysis showed that the median progression‐free survival was significantly longer in the osimertinib plus aspirin group than in the osimertinib group. In summary, aspirin synergistically enhances the antitumor activity of osimertinib in osimertinib‐resistant lung cancer cells through promoting Bim‐dependent apoptosis. This combination therapy may be effective in overcoming acquired resistance to osimertinib and prolonging survival in patients with NSCLC.

Highlights

IntroductionLung cancer is the leading cause of cancer-related death globally (Bray et al, 2018)
We evaluated whether aspirin in combination with osimertinib has synergistic antitumor activity using various in vitro and in vivo approaches, including the thiazolyl blue tetrazolium bromide (MTT) assay, flow cytometry, western blot assay, and xenografts
Due to the retention of EGFR T790M and no other resistance mechanism was detected at disease progression, these patients remained on osimertinib

Summary

Introduction

Lung cancer is the leading cause of cancer-related death globally (Bray et al, 2018). Epidermal growth factor receptor tyrosine kinase inhibitors (EGFRTKIs) offer significant clinical benefit for patients with EGFR mutations (Fukuoka et al, 2011; Zhou et al., 2011). Osimertinib, a third-generation EGFR-TKI, is currently the standard treatment for patients with progression after first- or second-generation EGFR-TKIs because of the T790M mutation or as a first-line treatment for EGFR mutation-positive advanced nonsmall-cell lung cancer (NSCLC) (Mok et al, 2017; Ramalingam et al, 2018; Soria et al, 2018). Molecular Oncology 14 (2020) 1152–1169 a 2020 The Authors.

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