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Targeted therapy is revolutionizing the treatment of cancers, but resistance evolves against these therapies and derogates their success. The phosphatidylinositol 3-kinase delta (PI3K-d) 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-d 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-d inhibitor. In the murine model, resistance to PI3K-d 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-d inhibitor resistance. IGF1R upregulation in PI3K-d inhibitor–resistant tumors was mediated by functional activation and enhanced nuclear localization of forkhead box protein O1 transcription factors and glycogen synthase kinase 3ß. 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-d inhibition. We also demonstrate that these pathway alterations can serve as therapeutic targets, because inhibition of IGF1R offered efficacious salvage treatment of PI3K-d inhibitor–resistant tumors in vitro and in vivo.

B cell receptor signaling (BCR) in chronic lymphocytic leukemia (CLL) drives tumor cell proliferation and survival. Inhibition of Bruton's tyrosine kinase (BTK), a key enzyme in the BCR pathway, has proved to be efficacious even in poor-risk and chemo-refractory patients. However resistance to the BTK inhibitor ibrutinib has been shown to emerge in a subset of CLL patients. Of importance, the C481S BTKmutation conferred resistance by preventing the covalent binding of ibrutinib to its target cysteine 481 in BTK. Vecabrutinib (formerly known as SNS-062, a succinate salt) is a novel, highly potent, next generation noncovalent BTK inhibitor which demonstrated biochemical and cellular activity against C481S BTK mutant in vitro. However, the efficacy of vecabrutinib and its impact on the T-cell microenvironment has not been studied in in vivopreclinical CLL models.

Lenalidomide is a highly active treatment for multiple myeloma. We and others have previously shown that lenalidomide targets Ikaros (IKZF1) and Aiolos (IKZF3) for ubiquitination and degradation via the cereblon (CRBN) E3 ubiquitin ligase. Depletion of these lymphoid transcription factors selectively inhibits growth of multiple myeloma cells. In contrast to human cells, mouse cells are insensitive to lenalidomide due to a single amino acid change in the murine CRBN (mCRBN) protein (isoleucine instead of valin at position 391). Therefore, lenalidomide could so far not be studied in syngenic mouse multiple myeloma models. The mouse MOPC-315.BM cell line engrafts in the bone marrow of BALB/c mice and induces multiple myeloma after intravenous injection (Riedel et al., PLoS one 2012 and Hofgaard et al., PLoS one 2012). We aimed to generate a lenalidomide-sensitive mouse model by retroviral expression of a mutant murine Crbnwhere the isoleucine at position 391 is replaced by valin (mCrbnI391V) in MOPC-315.BM cells.

Chronic lymphocytic leukemia (CLL) is characterized by continuously activated B-cell receptor (BCR) signaling. Phosphoinositide 3-kinase delta (PI3K-δ) is an important mediator of BCR signaling, which controls cell survival and proliferation through activation of AKT. The PI3K-δ inhibitor idelalisib (IDELA) is a highly effective treatment option for relapsed/refractory CLL patients. In the frontline setting, IDELA in treatment-naïve patients was associated with frequent adverse effects (AEs), such as an increased infection rate, colitis, and pneumonitis. Therefore, understanding the impact of PI3K-δ inhibition on the immune cells in the CLL microenvironment is of importance to identify novel treatment strategies to overcome these AEs.

Inhibitors of B-cell receptor (BCR) signaling have proven effective in the treatment of chronic lymphocytic leukemia (CLL). An important downstream mediator of BCR signaling is phosphoinositide 3-kinase delta (PI3Kd), which through activation of AKT, controls cell survival, growth and proliferation. Since it is expressed predominantly in cells of hematopoietic origin, PI3Kd is a promising target in CLL, and the novel PI3Kd inhibitor idelalisib is effective in treating relapsed/refractory CLL. However, a subset of patients relapse under therapy, and the mechanisms leading to resistance are not understood.