title: AKT-pathway inhibition in chronic lymphocytic leukemia reveals response relationships defined by 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 AKT-cascade 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-AKT-mTOR 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 tumor-selective 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 BCR-response 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.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Schrader
authors.forename: Wagma
authors.initials: W
authors.lastname: Popal
authors.forename: Nils
authors.initials: N
authors.lastname: Lilienthal
authors.forename: Giuliano
authors.initials: G
authors.lastname: Crispatzu
authors.forename: Petra
authors.initials: P
authors.lastname: Mayer
authors.forename: Dan
authors.initials: D
authors.lastname: Jones
authors.forename: Michael
authors.initials: M
authors.lastname: Hallek
authors.affiliation: Laboratory of Lymphocyte Signaling and Oncoproteome, Center for Integrated Oncology (CIO) Köln- Bonn and Cologne Cluster of Excellence in Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Germany. marco.herling@uk-koeln.de.
authors.forename: Marco
authors.initials: M
authors.lastname: Herling
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C090851:TCL1A protein, human; C546842:MTOR protein, human