Reference Detail

Ref Type

Journal Article

PMID

(30858154)

Authors

Weisner J, Landel I, Reintjes C, Uhlenbrock N, Trajkovic-Arsic M, Dienstbier N, Hardick J, Ladigan S, Lindemann M, Smith S, Quambusch L, Scheinpflug R, Depta L, Gontla R, Unger A, Müller H, Baumann M, Schultz-Fademrecht C, Günther G, Maghnouj A, Müller MP, Pohl M, Teschendorf C, Wolters H, Viebahn R, Tannapfel A, Uhl W, Hengstler JG, Hahn SA, Siveke JT, Rauh D

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	79	9	2019 05 01	2367-2378	Cancer Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Borussertib	Borussertib	4	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Borussertib			Akt1 Inhibitor 7	Borussertib is a covalent-allosteric inhibitor of AKT1, which reduces downstream signaling and potentially decreases tumor growth (PMID: 30858154).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PTEN L108R	breast cancer	sensitive	Capivasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Truqap (capivasertib) inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154).	30858154
PIK3CA H1047R	breast cancer	sensitive	Borussertib	Preclinical - Cell culture	Actionable	In a preclinical study, borussertib inhibited proliferation of a breast cancer cell line harboring PIK3CA H1047R in culture (PMID: 30858154).	30858154
PTEN L108R	breast cancer	sensitive	Borussertib	Preclinical - Cell culture	Actionable	In a preclinical study, borussertib inhibited AKT signaling and proliferation and increased apoptosis in a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154).	30858154
PIK3CA K111N	breast cancer	sensitive	Borussertib	Preclinical - Cell culture	Actionable	In a preclinical study, borussertib inhibited proliferation of a breast cancer cell line harboring PIK3CA K111N in culture (PMID: 30858154).	30858154
PTEN L108R	breast cancer	sensitive	Ipatasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Ipatasertib (GDC-0068) inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154).	30858154
PTEN L108R	breast cancer	sensitive	MK2206	Preclinical - Cell culture	Actionable	In a preclinical study, MK-2206 inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154).	30858154
PIK3CA E545K	breast cancer	sensitive	Borussertib	Preclinical - Cell culture	Actionable	In a preclinical study, borussertib inhibited AKT signaling and proliferation of a breast cancer cell line harboring PIK3CA E545K in culture (PMID: 30858154).	30858154
PTEN L108R	breast cancer	sensitive	Miransertib	Preclinical - Cell culture	Actionable	In a preclinical study, Miransertib (ARQ092) inhibited proliferation of a breast cancer cell line harboring PTEN L108R in culture (PMID: 30858154).	30858154