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

Gastrointestinal tumors; Tyrosine kinase inhibitors Tumores gastrointestinales; Inhibidores de la tirosina cinasa Tumors gastrointestinals; Inhibidors de la tirosina cinasa 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. This work was supported by Inserm Transfert (CoPoc N°; MAT-PI-13315-A-02 to SF), by the Association contre les Myopathies (AFM N° 23800 to SF), and by Ligue Régionale Contre le Cancer Languedoc-Roussillon (2020 to P.d.S.B). SRD is funded by the “Agence Nationale de la Recherche” (ANR-21-CE14-0017). This work was also supported by institutional funds from the University of Montpellier, INSERM, and CNRS.