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

## TL;DR

This study shows that combining inhibitors of Pim and PI3 kinases can effectively treat mature T-cell lymphoma by targeting escape mechanisms.

## Contribution

The study identifies a synergistic anti-lymphoma effect through dual inhibition of Pim and PI3 kinases, revealing a novel therapeutic strategy.

## Key findings

- PI3K/Akt-driven mTOR activation serves as an escape mechanism from Pim inhibition in mTCL cells.
- Dual inhibition of Pim and PI3 kinases synergistically reduces mTOR-induced protein translation and anti-apoptotic mechanisms.
- The dual inhibitor IBL-202 induces cell-cycle-dependent cell death in multiple mTCL subtypes.

## 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.