miR-6077 promotes cisplatin/pemetrexed resistance in lung adenocarcinoma via CDKN1A/cell cycle arrest and KEAP1/ferroptosis pathways

• Main Authors: Besskaya, V. (Author), Bi, G. (Author), Bian, Y. (Author), Chen, Z. (Author), Huang, Y. (Author), Jin, X. (Author), Liang, J. (Author), Lu, T. (Author), Tan, L. (Author), Wang, Q. (Author), Zhan, C. (Author), Zhang, H. (Author), Zhao, M. (Author), Zheng, Y. (Author)
• Format: Article
• Language: English
• Published: Cell Press 2022
• Subjects: cell-cycle arrest; chemoresistance; cisplatin; CRISPR-Cas9; ferroptosis; homology-directed repair; lncRNA; miRNA; MT: Non-coding RNAs; pemetrexed; RNA-seq
• Online Access: View Fulltext in Publisher

 Lung adenocarcinoma (LUAD) is one of the most common malignancies worldwide. Combination chemotherapy with cisplatin (CDDP) plus pemetrexed (PEM) remains the predominant therapeutic regimen; however, chemoresistance greatly limits its curative potential. Here, through CRISPR-Cas9 screening, we identified miR-6077 as a key driver of CDDP/PEM resistance in LUAD. Functional experiments verified that ectopic overexpression of miR-6077 desensitized LUAD cells to CDDP/PEM in both cell lines and patient-derived xenograft models. Through RNA sequencing in cells and single-cell sequencing of samples from patients with CDDP/PEM treatments, we observed CDDP/PEM-induced upregulation of CDKN1A and KEAP1, which in turn activated cell-cycle arrest and ferroptosis, respectively, thus leading to cell death. Through miRNA pull-down, we identified and validated that miR-6077 targets CDKN1A and KEAP1. Furthermore, we demonstrated that miR-6077 protects LUAD cells from cell death induced by CDDP/PEM via CDKN1A-CDK1-mediated cell-cycle arrest and KEAP1-NRF2-SLC7A11/NQO1-mediated ferroptosis, thus resulting in chemoresistance in multiple LUAD cells both in vitro and in vivo. Moreover, we found that GMDS-AS1 and LINC01128 sensitized LUAD cells to CDDP/PEM by sponging miR-6077. Collectively, these results imply the critical role of miR-6077 in LUAD's sensitivity to CDDP/PEM, thus providing a novel therapeutic strategy for overcoming chemoresistance in clinical practice. © 2022 The Author(s)