Altered splicing of ATG16‐L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non‐small cell lung cancer. Issue 19 (30th August 2022)

• Record Type: Journal Article
• Authors: Hatat, Anne‐Sophie; Benoit‐Pilven, Clara; Pucciarelli, Amélie; de Fraipont, Florence; Lamothe, Lucie; Perron, Pascal; Rey, Amandine; Levra, Matteo Giaj; Toffart, Anne‐Claire; Auboeuf, Didier; Eymin, Beatrice; Gazzeri, Sylvie
• Is Part Of: Molecular oncology. Volume 16:Issue 19(2022)
• Page Start: 3490
• Page End: 3508
• Publication Date: 2022-08-30
• Subjects: ATG16‐L1 -- autophagy -- EGFR‐TKI -- non‐small cell lung cancer -- resistance; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13229
• Languages: English
• ISSNs: 1574-7891

Abstract

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. Abstract : Chronic exposure of lung tumors to EGFR‐TKI induces deregulated splicing of ATG16‐L1 in favor of the β isoform that retains exon 8. This blocks the induction of autophagy in response to EGFR‐TKI and inhibits apoptosis thereby inducing resistance. Hence, correcting ATG16‐L1 splicing could represent a new therapeutic approach to overcome resistance to EGFR‐TKI.