Dual Targeting of Pim and PI3 Kinases in Mature T-Cell Lymphoma

Abstract

Provirus Integration site for Moloney leukemia virus (Pim) family members are well-known oncogenes, with an expression that is restricted to few cell types including hematopoietic cells in adult organisms, making it a promising target for lymphoma treatment. Indeed, previous studies in mature T-cell lymphoma (mTCL) cells revealed frequent upregulation of Pim expression. Nevertheless, inhibition of Pim kinases showed only minor effects on the viability of mTCL cells so far. Thus, we here addressed cellular responses to therapeutic inhibition of Pim kinases and identified a PI3K/Akt-driven activation of mTOR as a significant escape mechanism mitigating the anti-lymphoma effects of Pim inhibition. Indeed, dual inhibition of Pim and PI3 kinases showed synergistic anti-lymphoma effects in vitro through downregulation of mTOR-induced protein translation and mitigation of BCL-xL-mediated anti-apoptotic mechanisms. Based on this finding, we next explored the therapeutic potential of the dual Pim/PI3K inhibitor IBL-202 in mTCL cell lines. Strikingly, IBL-202 strongly induced cell-cycle-dependent cell death in cell lines of different mTCL subtypes. Together, our study provides mechanistic evidence supporting a therapeutic strategy of dual Pim- and PI3-kinase inhibition in mature T-cell lymphoma.