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

Abstract

Targeted therapy is revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The phosphatidylinositol 3-kinase delta (PI3K-δ) 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-δ 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-δ inhibitor. In the murine model, resistance to PI3K-δ 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-δ inhibitor resistance. IGF1R upregulation in PI3K-δ 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 signaling cascades play a predominant role in the resistance and survival of cancer cells under PI3K-δ inhibition. We also demonstrate that these pathway alterations can serve as therapeutic targets, because inhibition of IGF1R offered efficacious salvage treatment of PI3K-δ inhibitor–resistant tumors in vitro and in vivo.

Drug Resistance in Non-Hodgkin Lymphomas

“…Insulin-like growth factor 1 receptor (IGF1R) was associated with intrinsic resistance to idelalisib in tumor cells [135]. IGF1R, associated with trisomy 12 in CLL cells, represents a druggable target offering potential combinatorial and salvage treatment [136]. IL6-triggered Janus kinase(JAK)-signal transducer and activator of transcription (STAT) cascade was reported as a critical molecular mechanism underlying resistance of lymphoma cells to copanlisib and duvelisib [137].…”

Genetic and Non-Genetic Mechanisms of Resistance to BCR Signaling Inhibitors in B Cell Malignancies

“…Unfortunately, unlike in ibrutinib treated patients, the mechanisms of resistance remain mostly unclear ( 8 , 206 ). No recurrent mutations were found in patients progressing on idelalisib nor have they been found in a mouse model resistant to PI3K5 inhibition ( 207 , 208 ). Two studies have shown the role of MAPK signaling in resisting PI3K5 inhibition.…”

“…Secondly, a nongenetic mechanism of resistance was found in PI3K5 resistant mice, where the upregulation of insulin-like growth factor 1 receptor (IGF1R) led to MAPK signaling activation. IGF1R upregulation was caused by FoxO1 and GSK3β and the resistance was resolved by inhibiting the receptor with linsitinib ( 208 ). Initial experiments with copanlisib point to IL6 signaling as a main player in copanlisib resistance; levels of IL6 and phosphorylation of STAT5, Akt, p70S6K, and MAPK were increased in copanlisib-resistant B cell lymphoma cell lines and the resistance was reversible by JAK inhibitor ( 210 ).…”

Revolution of Chronic Lymphocytic Leukemia Therapy: the Chemo-Free Treatment Paradigm

“…Acquired resistance to idelalisib treatment has been observed in humans, although no unique recurrent mutation was identified [40]. Preclinical data show that resistance to PI3Kδ inhibition does not rely on a unique mutation, though resistance to PI3Kδ inhibition induces a relevant activation of IGF1R, resulting in enhanced MAPK signaling [41].…”