Universität zu Köln

Schrader, Alexandra, Popal, Wagma, Lilienthal, Nils, Crispatzu, Giuliano, Mayer, Petra, Jones, Dan, Hallek, Michael and Herling, Marco (2014). AKT-pathway Inhibition in Chronic Lymphocytic Leukemia Reveals Response Relationships Defined by TCL1. Curr. Cancer Drug Targets, 14 (8). S. 700 - 713. SHARJAH: BENTHAM SCIENCE PUBL LTD. ISSN 1873-5576

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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 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 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schrader, Alexandra UNSPECIFIED UNSPECIFIED UNSPECIFIED Popal, Wagma UNSPECIFIED UNSPECIFIED UNSPECIFIED Lilienthal, Nils UNSPECIFIED UNSPECIFIED UNSPECIFIED Crispatzu, Giuliano UNSPECIFIED UNSPECIFIED UNSPECIFIED Mayer, Petra UNSPECIFIED UNSPECIFIED UNSPECIFIED Jones, Dan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hallek, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Herling, Marco UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-449298
DOI:	10.2174/1568009614666141028101711
Journal or Publication Title:	Curr. Cancer Drug Targets
Volume:	14
Number:	8
Page Range:	S. 700 - 713
Date:	2014
Publisher:	BENTHAM SCIENCE PUBL LTD
Place of Publication:	SHARJAH
ISSN:	1873-5576
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language B-CELL RECEPTOR; RAPAMYCIN INHIBITOR; PROTOONCOGENE TCL1; KINASE-ACTIVITY; DRUG DISCOVERY; STROMAL CELLS; EXPRESSION; CANCER; LYMPHOMA; MOUSE Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/44929