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You are here: Home / Teams / Regulation of Genome Architecture and Dynamics of Splicing (ReGArDS) - D. Auboeuf and C. Bourgeois / Publications / Altered splicing of ATG16-L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer.

Altered splicing of ATG16-L1 mediates acquired resistance to tyrosine kinase inhibitors of EGFR by blocking autophagy in non-small cell lung cancer.

Anne-Sophie Hatat, Clara Benoit-Pilven, Amélie Pucciarelli, Florence de Fraipont, Lucie Lamothe, Pascal Perron, Amandine Rey, Matteo G Levra, Anne-Claire Toffart, Didier Auboeuf, Beatrice Eymin, and Sylvie Gazzeri (2022)

Mol Oncol.

Despite the initial efficacy of using tyrosine kinase inhibitors of epidermalgrowth factor receptors (EGFR-TKIs) for treating patients with non-small celllung cancer (NSCLC), resistance inevitably develops. Recent studies highlight alink between alternative splicing and cancer drug response. Therefore, we aimedto identify deregulated splicing events that play a role in resistance toEGFR-TKI. By using RNA sequencing, reverse-transcription PCR (RT-PCR), and RNAinterference, we showed that overexpression of a splice variant of the autophagicgene ATG16-L1 that retains exon 8 and encodes the β-isoform of autophagy-relatedprotein 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 ofprogression in 3 of 11 NSCLC patients treated with EGFR-TKI. Mechanistically,gefitinib-induced autophagy was impaired in resistant cells that accumulatedATG16-L1 β. Neutralization of ATG16-L1 β restored autophagy in response togefitinib, induced apoptosis, and inhibited the growth of in ovo tumorxenografts. Conversely, overexpression of ATG16-L1 β in parental sensitive cellsprevented gefitinib-induced autophagy and increased cell survival. These resultssupport a role of defective autophagy in acquired resistance to EGFR-TKIs andidentify splicing regulation of ATG16-L1 as a therapeutic vulnerability thatcould be explored for improving EGFR-targeted cancer therapy.

 
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