IGF1R as druggable target mediating PI3K-{delta} inhibitor resistance in a murine model of chronic lymphocytic leukemia

Targeted therapy is revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The phosphatidylinositol 3-kinase delta (PI3K-) inhibitor idelalisib has been approved for treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma, but the mechanisms conferring resistance in a subset of patients are unknown. Here, we modeled resistance to PI3K- inhibitor in vivo using a serial tumor transfer and treatment scheme in mice. Whole-exome sequencing did not identify any recurrent mutation explaining resistance to PI3K- inhibitor. In the murine model, resistance to PI3K- inhibitor occurred as a result of a signaling switch mediated by consistent and functionally relevant activation of insulin-like growth factor 1 receptor (IGF1R), resulting in enhanced MAPK signaling in the resistant tumors. Overexpression of IGF1R in vitro demonstrated its prominent role in PI3K- inhibitor resistance. IGF1R upregulation in PI3K- inhibitor–resistant tumors was mediated by functional activation and enhanced nuclear localization of forkhead box protein O1 transcription factors and glycogen synthase kinase 3β. In human CLL, high IGF1R expression was associated with trisomy 12. CLL cells from an idelalisib-treated patient showed decreased sensitivity to idelalisib in vitro concomitant with enhanced MAPK signaling and strong upregulation of IGF1R upon idelalisib exposure. Thus, our results highlight that alternative signali...

Source: Blood - August 7, 2019 Category: Hematology Authors: Scheffold, A., Jebaraj, B. M. C., Tausch, E., Bloehdorn, J., Ghia, P., Yahiaoui, A., Dolnik, A., Blätte, T. J., Bullinger, L., Dheenadayalan, R. P., Li, L., Schneider, C., Chen, S.-S., Chiorazzi, N., Dietrich, S., Seiffert, M., Tannheimer, S., Do& Tags: Lymphoid Neoplasia Source Type: research