AKT-pathway Inhibition in Chronic Lymphocytic Leukemia Reveals Response Relationships Defined by TCL1

Title:AKT-pathway Inhibition in Chronic Lymphocytic Leukemia Reveals Response Relationships Defined by TCL1

Volume: 14 Issue: 8

Author(s): Alexandra Schrader, Wagma Popal, Nils Lilienthal, Giuliano Crispatzu, Petra Mayer, Dan Jones, Michael Hallek and Marco Herling

Affiliation:

Keywords: AKT, CLL, inhibitor response, mTOR, PI3K, TCL1.

Abstract: Cell survival in chronic lymphocytic leukemia (CLL) largely depends on B-cell receptor-induced AKT activation. Gain-of-function genomic lesions of PI3K-AKT-mTOR pathway components are usually absent in CLL. We previously established that a BCR-mediated growth response in CLL is determined by the oncogene T-cell leukemia 1 (TCL1) through a sensitizer effect on AKT phospho-activation. Despite high clinical response rates following AKTcascade inhibition in CLL, resistances in a substantial proportion of patients call for reliable pre- and post-exposure strata to better predict compound responses. Using a panel of inhibitors with differential vertical affinities in the PI3K-AKTmTOR axis, we describe distinct patterns and determinants of sensitivities in 75 CLL samples. The compounds specifically impacted the BCR-induced physical TCL1-AKT interaction. In general, there was an efficient and tumorselective abrogation of cell survival in suspension or protective stromal-cell cultures. However, biochemical and survival responses were heterogeneous across CLL and showed only incomplete overlap across inhibitors. Sensitivity clusters could be defined by differential responses to selective pan-PI3K inhibition vs. compounds acting more down-stream. An elevated PI3K/AKT/mTOR activation state conferred sensitivity or resistance, depending on the applied inhibitor. In fact, down-stream interception by mTOR or dual mTOR/PI3K inhibition appears more efficient in cases expressing the BCRresponse and poor-risk determinants of ZAP70 or TCL1. Finally, exploiting the TCL1-AKT interaction, peptide-based TCL1-interphase mimics were potent in steric AKT antagonization and in reducing CLL cell survival. Overall, this study provides informative response relationships in AKT-pathway interception that can help refining predictive models in BCR-pathway inhibition in CLL.

Cite this article as:

Schrader Alexandra, Popal Wagma, Lilienthal Nils, Crispatzu Giuliano, Mayer Petra, Jones Dan, Hallek Michael and Herling Marco, AKT-pathway Inhibition in Chronic Lymphocytic Leukemia Reveals Response Relationships Defined by TCL1, Current Cancer Drug Targets 2014; 14 (8) . https://dx.doi.org/10.2174/1568009614666141028101711