Preclinical efficacy of covalent-allosteric AKT inhibitor borussertib in combination with trametinib in KRAS-mutant pancreatic and colorectal cancer

Jorn Weisner, Ina Landel, Christoph Reintjes, Niklas Uhlenbrock, Marija Trajkovic-Arsic, Niklas Dienstbier, Julia Hardick, Swetlana Ladigan, Marius Lindemann, Steven Smith, Lena Quambusch, Rebekka Scheinpflug, Laura Depta, Rajesh Gontla, Anke Unger, Heiko Muller, Matthias Baumann, Carsten Schultz-Fademrecht, Georgia Gunther, Abdelouahid MaghnoujMatthias P. Muller, Michael Pohl, Christian Teschendorf, Heiner Wolters, Richard Viebahn, Andrea Tannapfel, Waldemar Uhl, Jan G. Hengstler, Stephan A. Hahn, Jens T. Siveke, Daniel Rauh

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Aberrations within the PI3K/AKT signaling axis are frequently observed in numerous cancer types, highlighting the relevance of these pathways in cancer physiology and pathology. However, therapeutic interventions employing AKT inhibitors often suffer from limitations associated with target selectivity, efficacy, or dose-limiting effects. Here we present the first crystal structure of autoinhibited AKT1 in complex with the covalent-allosteric inhibitor borussertib, providing critical insights into the structural basis of AKT1 inhibition by this unique class of compounds. Comprehensive biological and preclinical evaluation of borussertib in cancer-related model systems demonstrated a strong antiproliferative activity in cancer cell lines harboring genetic alterations within the PTEN, PI3K, and RAS signaling pathways. Furthermore, borussertib displayed antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models of mutant KRAS pancreatic and colon cancer. Significance: Borussertib, a first-in-class covalent-allosteric AKT inhibitor, displays antitumor activity in combination with the MEK inhibitor trametinib in patient-derived xenograft models and provides a starting point for further pharmacokinetic/ dynamic optimization.

Original languageEnglish
Pages (from-to)2367-2378
Number of pages12
JournalCancer Research
Volume79
Issue number9
DOIs
StatePublished - 2019
Externally publishedYes

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