Preclinical Efficacy of Covalent-Allosteric AKT Inhibitor Borussertib in Combination with Trametinib in KRAS-Mutant Pancreatic and Colorectal Cancer

被引：63

作者：

Weisner, Joern ^{[1
,2
]}

Landel, Ina ^{[1
,2
]}

Reintjes, Christoph ^{[3
]}

Uhlenbrock, Niklas ^{[1
,2
]}

Trajkovic-Arsic, Marija ^{[4
,5
,6
]}

Dienstbier, Niklas ^{[4
,5
,6
]}

Hardick, Julia ^{[1
,2
]}

Ladigan, Swetlana ^{[3
]}

Lindemann, Marius ^{[1
,2
]}

Smith, Steven ^{[1
,2
,15
]}

Quambusch, Lena ^{[1
,2
]}

Scheinpflug, Rebekka ^{[1
,2
]}

Depta, Laura ^{[1
,2
]}

Gontla, Rajesh ^{[1
,2
]}

Unger, Anke ^{[7
]}

Mueller, Heiko ^{[7
,16
]}

Baumann, Matthias ^{[7
]}

Schultz-Fademrecht, Carsten ^{[7
]}

Guenther, Georgia ^{[8
]}

Maghnouj, Abdelouahid ^{[3
]}

Mueller, Matthias P. ^{[1
,2
]}

Pohl, Michael ^{[9
]}

Teschendorf, Christian ^{[10
]}

Wolters, Heiner ^{[11
]}

Viebahn, Richard ^{[12
]}

Tannapfel, Andrea ^{[13
]}

Uhl, Waldemar ^{[14
]}

Hengstler, Jan G. ^{[8
]}

Hahn, Stephan A. ^{[3
]}

Siveke, Jens T. ^{[4
,5
,6
]}

Rauh, Daniel ^{[1
,2
]}

机构：

[1] TU Dortmund Univ, Fac Chem & Chem Biol, Dortmund, Germany

[2] ZIW, DDHD, Dortmund, Germany

[3] Ruhr Univ Bochum, Dept Mol Gastrointestinal Oncol, Univ Str 150, D-44780 Bochum, Germany

[4] German Canc Consortium DKTK, Heidelberg, Germany

[5] German Canc Res Ctr, Heidelberg, Germany

[6] Univ Hosp Essen, Div Solid Tumor Translat Oncol, German Canc Consortium DKTK, Partner Site Essen,West German Canc Ctr, Hufelandstr 55, D-45147 Essen, Germany

[7] Lead Discovery Ctr GmbH, Dortmund, Germany

[8] TU Dortmund Univ, Leibniz Res Ctr Working Environm & Human Factors, Dortmund, Germany

[9] Ruhr Univ Bochum, Dept Internal Med, Knappschaftskrankenhaus, Bochum, Germany

[10] St Josefs Hosp, Dept Internal Med, Dortmund, Germany

[11] St Josefs Hosp, Dept Visceral & Gen Surg, Dortmund, Germany

[12] Ruhr Univ Bochum, Dept Surg, Knappschaftskrankenhaus, Bochum, Germany

[13] Ruhr Univ Bochum, Inst Pathol, Bochum, Germany

[14] Ruhr Univ Bochum, St Josef Hosp, Dept Visceral & Gen Surg, Bochum, Germany

[15] Agap2 Life Sci, D-60323 Frankfurt, Germany

[16] Saltigo GmbH Chempk, Bldg Q 18-2, D-51369 Leverkusen, Germany

来源：

CANCER RESEARCH | 2019年 / 79卷 / 09期

关键词：

PATHWAY; TARGETS; INSIGHTS; MUTATION; THERAPY; TUMORS;

D O I：

10.1158/0008-5472.CAN-18-2861

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 anti-proliferative 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.

引用

页码：2367 / 2378

页数：12

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