Reference Detail

Ref Type

Journal Article

PMID

(22294718)

Authors

Davies BR, Greenwood H, Dudley P, Crafter C, Yu DH, Zhang J, Li J, Gao B, Ji Q, Maynard J, Ricketts SA, Cross D, Cosulich S, Chresta CC, Page K, Yates J, Lane C, Watson R, Luke R, Ogilvie D, Pass M

Title

Preclinical pharmacology of AZD5363, an inhibitor of AKT: pharmacodynamics, antitumor activity, and correlation of monotherapy activity with genetic background.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	11	4	2012 Apr	873-87	Mol Cancer Ther

URL

Abstract Text

AKT is a key node in the most frequently deregulated signaling network in human cancer. AZD5363, a novel pyrrolopyrimidine-derived compound, inhibited all AKT isoforms with a potency of 10 nmol/L or less and inhibited phosphorylation of AKT substrates in cells with a potency of approximately 0.3 to 0.8 μmol/L. AZD5363 monotherapy inhibited the proliferation of 41 of 182 solid and hematologic tumor cell lines with a potency of 3 μmol/L or less. Cell lines derived from breast cancers showed the highest frequency of sensitivity. There was a significant relationship between the presence of PIK3CA and/or PTEN mutations and sensitivity to AZD5363 and between RAS mutations and resistance. Oral dosing of AZD5363 to nude mice caused dose- and time-dependent reduction of PRAS40, GSK3β, and S6 phosphorylation in BT474c xenografts (PRAS40 phosphorylation EC(50) ~ 0.1 μmol/L total plasma exposure), reversible increases in blood glucose concentrations, and dose-dependent decreases in 2[18F]fluoro-2-deoxy-D-glucose ((18)F-FDG) uptake in U87-MG xenografts. Chronic oral dosing of AZD5363 caused dose-dependent growth inhibition of xenografts derived from various tumor types, including HER2(+) breast cancer models that are resistant to trastuzumab. AZD5363 also significantly enhanced the antitumor activity of docetaxel, lapatinib, and trastuzumab in breast cancer xenografts. It is concluded that AZD5363 is a potent inhibitor of AKT with pharmacodynamic activity in vivo, has potential to treat a range of solid and hematologic tumors as monotherapy or a combinatorial agent, and has potential for personalized medicine based on the genetic status of PIK3CA, PTEN, and RAS. AZD5363 is currently in phase I clinical trials.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
Click on any column header arrows to sort by that column
Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.

Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
Capivasertib	Capivasertib	20	6

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
Capivasertib	Truqap	AZD5363\|AZD 5363\|AZD-5363	Akt Inhibitor (Pan) 21	Truqap (capivasertib) decreases PI3K/AKT/mTOR signaling by inhibition of AKT1, AKT2, and AKT3, potentially resulting in decreased cell proliferation (PMID: 22294718, PMID: 32532747, PMID: 32312891). Truqap (capivasertib) in combination with Faslodex (fulvestrant) is FDA-approved for use in patients with hormone receptor-positive, ERBB2 (HER2)-negative, locally advanced or metastatic breast cancer with one or more PIK3CA/AKT1/PTEN-alterations (FDA.gov).

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 inact mut	Advanced Solid Tumor	sensitive	Capivasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Truqap (capivasertib) inhibited growth of various solid tumor cell culture models with inactivating Pten mutations (PMID: 22294718).	22294718
PTEN loss	Advanced Solid Tumor	sensitive	Capivasertib	Preclinical - Cell culture	Actionable	In a preclinical study, Truqap (capivasertib) inhibited growth of various solid tumor cell culture models with loss of Pten (PMID: 22294718).	22294718
PIK3CA mutant	breast cancer	predicted - sensitive	Capivasertib	Preclinical	Actionable	In a preclinical study, Truqap (capivasertib) inhibited growth in breast cancer cell lines and xenograft models expressing PIK3CA mutations (PMID: 22294718).	22294718
PTEN loss	renal carcinoma	sensitive	Capivasertib	Preclinical - Pdx	Actionable	In a preclinical study, Truqap (capivasertib) inhibited growth of renal cancer Pdx models with Pten loss (PMID: 22294718).	22294718