Ankyrin Repeat Domain 1 Overexpression is Associated with Common Resistance to Afatinib and Osimertinib in EGFR-mutant Lung Cancer

• Published in: Scientific reports Vol. 8; no. 1; pp. 14896 - 9
• Main Authors: Takahashi, Akiko, Seike, Masahiro, Chiba, Mika, Takahashi, Satoshi, Nakamichi, Shinji, Matsumoto, Masaru, Takeuchi, Susumu, Minegishi, Yuji, Noro, Rintaro, Kunugi, Shinobu, Kubota, Kaoru, Gemma, Akihiko
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 05.10.2018; Nature Publishing Group UK; Nature Portfolio
• Subjects: A549 Cells; Acrylamides - pharmacology; Adenocarcinoma; Afatinib; Afatinib - pharmacology; Aniline Compounds - pharmacology; Ankyrin Repeat Domain (ANKRD1); Ankyrins; Antineoplastic Agents - pharmacology; Apoptosis; Carcinoma, Non-Small-Cell Lung - drug therapy; DNA microarrays; Drug Resistance, Neoplasm; EGFR-mutant NSCLC Patients; Epidermal growth factor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors (EGFR-TKIs); Epidermal growth factor receptors; Epithelial-Mesenchymal Transition - drug effects; ErbB Receptors - antagonists & inhibitors; Female; Gene expression; Humans; Imatinib; Imatinib Mesylate - pharmacology; Lung cancer; Lung Neoplasms - drug therapy; Male; Mesenchyme; miRNA; mRNA; Muscle Proteins - genetics; Muscle Proteins - metabolism; Mutation - drug effects; Non-small cell lung carcinoma; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Osimertinib; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase receptors; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction - drug effects; Targeted cancer therapy; Therapeutic applications; Tumor cell lines
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-33190-8

Overcoming acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is critical in combating EGFR-mutant non-small cell lung cancer (NSCLC). We tried to construct a novel therapeutic strategy to conquer the resistance to second-and third-generation EGFR-TKIs in EGFR-positive NSCLC patients. We established afatinib- and osimertinib-resistant lung adenocarcinoma cell lines. Exome sequencing, cDNA array and miRNA microarray were performed using the established cell lines to discover novel therapeutic targets associated with the resistance to second-and third-generation EGFR-TKIs. We found that ANKRD1 which is associated with the epithelial-mesenchymal transition (EMT) phenomenon and anti-apoptosis, was overexpressed in the second-and third-generation EGFR-TKIs-resistant cells at the mRNA and protein expression levels. When ANKRD1 was silenced in the EGFR-TKIs-resistant cell lines, afatinib and osimertinib could induce apoptosis of the cell lines. Imatinib could inhibit ANKRD1 expression, resulting in restoration of the sensitivity to afatinib and osimertinib of EGFR-TKI-resistant cells. In EGFR-mutant NSCLC patients, ANKRD1 was overexpressed in the tumor after the failure of EGFR-TKI therapy, especially after long-duration EGFR-TKI treatments. ANKRD1 overexpression which was associated with EMT features and anti-apoptosis, was commonly involved in resistance to second-and third-generation EGFR-TKIs. ANKRD1 inhibition could be a promising therapeutic strategy in EGFR-mutant NSCLC patients.