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

Abstract

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.

IGFBP7 Drives Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibition in Lung Cancer

“…To identify the genes associated with TKI resistance, we collected four gene expression datasets consisting of 15 experiments to compare TKI-sensitive to TKI-resistant cells, and calculated the TKI resistance-related score for each gene based on its expression (Table S1) [13,14,15]. In each dataset, corresponding TKI-resistant cell lines were generated from TKI-sensitive cell lines (PC9, HCC827, and HCC4006) subjected to long-term treatment with EGFR TKIs, including gefitinib, erlotinib, afatinib, and osimertinib.…”

Ectopic Expression of Ankrd2 Affects Proliferation, Motility and Clonogenic Potential of Human Osteosarcoma Cells

“…Moreover, an emerging role for Ankrd2-homolog Ankrd1 in cancer development has been proposed. A remarkable number of papers have demonstrated that Ankrd1 is involved in the progression of cancers such as those afflicting ovaries [ 23 ], breast [ 24 ], pancreas [ 25 ] and in the chemoresistance of lung cancer [ 26 ].…”

Aspirin sensitizes osimertinib‐resistant NSCLC cells in vitro and in vivo via Bim‐dependent apoptosis induction

“…Cell viability was assessed using MTT assays (Takahashi et al , 2018). Cells were seeded at 2000 cells per well in 96‐well plates and incubated in RPMI‐1640 + 10% FBS.…”