LIX1 Controls MAPK Signaling Reactivation and Contributes to GIST-T1 Cell Resistance to Imatinib

Gastrointestinal stromal tumor (GIST), the most common sarcoma, is mainly caused by an oncogenic mutation in the KIT receptor tyrosine kinase. Targeting KIT using tyrosine kinase inhibitors, such as imatinib and sunitinib, provides substantial benefit; however, in most patients, the disease will eve...

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Bibliographic Details
Published in:	International journal of molecular sciences Vol. 24; no. 8; p. 7138
Main Authors:	Ruiz-Demoulin, Salomé, Trenquier, Eva, Dekkar, Sanaa, Deshayes, Sébastien, Boisguérin, Prisca, Serrano, César, de Santa Barbara, Pascal, Faure, Sandrine
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 01-04-2023 MDPI
Subjects:	Antineoplastic Agents - pharmacology Antineoplastic Agents - therapeutic use Autophagy-Related Proteins - genetics Biochemistry, Molecular Biology Cancer Care and treatment Development and progression Drug Resistance, Neoplasm - genetics Gastrointestinal Stromal Tumors - drug therapy Gastrointestinal Stromal Tumors - genetics Gastrointestinal Stromal Tumors - pathology gastrointestinal tumors Genetic aspects Genomics Human health and pathology Humans Hépatology and Gastroenterology Imatinib Mesylate - pharmacology Imatinib Mesylate - therapeutic use Life Sciences LIX1 resistance MAP Kinase Signaling System MAPK Mutation Pharmaceutical sciences Pharmacology Protein Kinase Inhibitors - pharmacology Proto-Oncogene Proteins c-kit - metabolism Sarcoma Sunitinib - pharmacology Sunitinib - therapeutic use Tyrosine tyrosine kinase inhibitors France tyrosine kinase inhibitors LIX1 resistance MAPK gastrointestinal tumors
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Summary:	Gastrointestinal stromal tumor (GIST), the most common sarcoma, is mainly caused by an oncogenic mutation in the KIT receptor tyrosine kinase. Targeting KIT using tyrosine kinase inhibitors, such as imatinib and sunitinib, provides substantial benefit; however, in most patients, the disease will eventually progress due to KIT secondary mutations leading to treatment failure. Understanding how GIST cells initially adapt to KIT inhibition should guide the selection of appropriate therapies to overcome the emergence of resistance. Several mechanisms have been broadly implicated in the resistance to imatinib anti-tumoral effects, including the reactivation of MAPK signaling upon KIT/PDGFRA targeted inhibition. This study provides evidence that LImb eXpression 1 (LIX1), a protein we identified as a regulator of the Hippo transducers YAP1 and TAZ, is upregulated upon imatinib or sunitinib treatment. LIX1 silencing in GIST-T1 cells impaired imatinib-induced MAPK signaling reactivation and enhanced imatinib anti-tumor effect. Our findings identified LIX1 as a key regulator of the early adaptative response of GIST cells to targeted therapies.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC10138740 These authors contributed equally to the work.
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms24087138