The Association of Annexin A1 and Chemosensitivity to Osimertinib in Lung Cancer Cells.

Min-Chun Chuang,Ming-Szu Hung,Ya-Chin Li,Jr-Hau Lung,Yi-Chuan Chen,Yu-Ching Lin

doi:10.3390/cancers13164106

Abstract

Simple SummaryAnnexin A1 (ANXA1) is associated with the growth and resistance to chemotherapy drugs in lung cancer cells. In this study, the association of ANXA1 with chemosensitivity to Osimertinib, a third generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) was studied. The knockdown of ANXA1 increased chemosensitivity to Osimertinib and decreased tumorigenesis, invasion and migration of lung cancer cells with EGFR mutations. The study showed that ANXA1 plays critical roles in chemosensitivity to Osimertinib in lung cancer cells with EGFR mutations.Annexin A1 (ANXA1) has been reported to promote tumor growth and resistance to chemotherapy drugs in lung cancer cells. In this study, we focused on the association of ANXA1 and chemosensitivity with a third generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), Osimertinib, in lung cancer cells with EGFR mutations. The overexpression of ANXA1 was observed in the lung cancer cells studied. The downregulation of ANXA1 with small interference RNA (siRNA) decreased the growth of lung cancer cells. In lung cancer cells with EGFR mutations, the knockdown of ANXA1 increased the chemosensitivity to Osimertinib, and decreased the tumorigenesis, invasion and migration of lung cancer cells. Further study showed that the knockdown of ANXA1 inhibited the phosphorylation of EGFR and down-stream Akt pathways and promoted apoptosis in lung cancer cells treated with Osimertinib. A mice xenograft lung cancer model was established in our study and showed that ANXA1 siRNA enhanced the effects of Osimertinib in vivo. Our study results showed that ANXA1 plays critical roles in chemosensitivity to EGFR-TKI in lung cancer cells with the EGFR mutation. Our efforts may be used in the development of lung cancer treatment strategies in the future.

Highlights

Lung cancer remains the leading cause of cancer deaths in the world
We examined the expression of Annexin A1 (ANXA1) in non-small cell lung cancer (NSCLC) lung cancer cells using Western blot analysis
The results showed that among the six lung cancer cell lines, all cell lines (A549, H460, H1650, H1975, H157, PC9 and H1703) expressed ANXA1 at levels substantially higher than those expressed by normal human fetal lung fibroblast cells (WI-38) (Figure 1A)

Summary

Introduction

Lung cancer remains the leading cause of cancer deaths in the world. At the time of diagnosis, most lung patients are in the advanced stage of the disease. In non-small cell lung cancer (NSCLC), the EGFR tyrosine kinase (TK) domain mutations in cancer cells are strongly associated with a higher sensitivity to EGFR tyrosine kinase inhibitor (TKI). EGFR mutations in NSCLC are usually present on exons 18–21 of the EGFR gene. Even with the activating mutation, patients developed resistance to EGFR-TKI after a certain period of treatment. The most common secondary mutation, detected in approximately 60% of the acquired resistance developed to first-line EGFR-TKIs, is the T790M mutation in exon 20 of the EGFR gene [8]. The T790M resistance can be overcome by using third-generation EGFR tyrosine kinase inhibitors, such as Osimertinib. The T790M mutation-positive advanced NSCLC initially responding to Osimertinib usually develops resistance to treatment, with a progression-free survival ranging from 9.7 to 11 months [9]. It is necessary to develop novel treatments to overcome Osimertinib resistance in the present era

Methods

Results

Conclusion