TY - JOUR
T1 - Preclinical efficacy of covalent-allosteric AKT inhibitor borussertib in combination with trametinib in KRAS-mutant pancreatic and colorectal cancer
AU - Weisner, Jorn
AU - Landel, Ina
AU - Reintjes, Christoph
AU - Uhlenbrock, Niklas
AU - Trajkovic-Arsic, Marija
AU - Dienstbier, Niklas
AU - Hardick, Julia
AU - Ladigan, Swetlana
AU - Lindemann, Marius
AU - Smith, Steven
AU - Quambusch, Lena
AU - Scheinpflug, Rebekka
AU - Depta, Laura
AU - Gontla, Rajesh
AU - Unger, Anke
AU - Muller, Heiko
AU - Baumann, Matthias
AU - Schultz-Fademrecht, Carsten
AU - Gunther, Georgia
AU - Maghnouj, Abdelouahid
AU - Muller, Matthias P.
AU - Pohl, Michael
AU - Teschendorf, Christian
AU - Wolters, Heiner
AU - Viebahn, Richard
AU - Tannapfel, Andrea
AU - Uhl, Waldemar
AU - Hengstler, Jan G.
AU - Hahn, Stephan A.
AU - Siveke, Jens T.
AU - Rauh, Daniel
N1 - Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85065516542&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-18-2861
DO - 10.1158/0008-5472.CAN-18-2861
M3 - Article
C2 - 30858154
AN - SCOPUS:85065516542
SN - 0008-5472
VL - 79
SP - 2367
EP - 2378
JO - Cancer Research
JF - Cancer Research
IS - 9
ER -
