In:
Molecular Oncology, Wiley, Vol. 16, No. 19 ( 2022-10), p. 3490-3508
Abstract:
Despite the initial efficacy of using tyrosine kinase inhibitors of epidermal growth factor receptors (EGFR‐TKIs) for treating patients with non‐small cell lung cancer (NSCLC), resistance inevitably develops. Recent studies highlight a link between alternative splicing and cancer drug response. Therefore, we aimed to identify deregulated splicing events that play a role in resistance to EGFR‐TKI. By using RNA sequencing, reverse‐transcription PCR (RT‐PCR), and RNA interference, we showed that overexpression of a splice variant of the autophagic gene ATG16‐L1 that retains exon 8 and encodes the β‐isoform of autophagy‐related protein 16‐1 (ATG16‐L1 β) concurs acquired resistance to EGFR‐TKI in NSCLC cells. Using matched biopsies, we found increased levels of ATG16‐L1 β at the time of progression in 3 of 11 NSCLC patients treated with EGFR‐TKI. Mechanistically, gefitinib‐induced autophagy was impaired in resistant cells that accumulated ATG16‐L1 β. Neutralization of ATG16‐L1 β restored autophagy in response to gefitinib, induced apoptosis, and inhibited the growth of in ovo tumor xenografts. Conversely, overexpression of ATG16‐L1 β in parental sensitive cells prevented gefitinib‐induced autophagy and increased cell survival. These results support a role of defective autophagy in acquired resistance to EGFR‐TKIs and identify splicing regulation of ATG16‐L1 as a therapeutic vulnerability that could be explored for improving EGFR‐targeted cancer therapy.
Type of Medium:
Online Resource
ISSN:
1574-7891
,
1878-0261
DOI:
10.1002/1878-0261.13229
Language:
English
Publisher:
Wiley
Publication Date:
2022
detail.hit.zdb_id:
2322586-5
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