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Ref Type Journal Article
PMID (24088382)
Authors Li J, Davies BR, Han S, Zhou M, Bai Y, Zhang J, Xu Y, Tang L, Wang H, Liu YJ, Yin X, Ji Q, Yu DH
Title The AKT inhibitor AZD5363 is selectively active in PI3KCA mutant gastric cancer, and sensitizes a patient-derived gastric cancer xenograft model with PTEN loss to Taxotere.
Journal Journal of translational medicine
Vol 11
Issue
Date 2013 Oct 02
URL
Abstract Text Activation of the PI3K/AKT pathway is a common phenomenon in cancer due to multiple mechanisms, including mutation of PI3KCA, loss or mutation of PTEN, or over-expression of receptor tyrosine kinases. We recently developed a novel AKT kinase inhibitor, AZD5363, and demonstrated that HGC27, a cell line harboring both PI3KCA mutation and PTEN loss, displayed the greatest sensitivity to this AKT inhibitor in vitro and in vivo.To further elucidate the correlation between AZD5363 response and genetic alterations in gastric cancer (GC) and identify GC patients with both PI3KCA mutations and PTEN loss, we investigated the effects of pharmacological inhibition of AKT on a panel of 20 GC cell lines and genetic aberrations in tumor samples from a cohort of Chinese GC patients. We demonstrated that GC cells with PI3KCA mutations were selectively sensitive to AZD5363. Disease linkage studies showed that PI3KCA activating mutations or PTEN loss were found in 2.7% (4/150) and 23% (14/61) of Chinese GC patients respectively. To further dissect the role of PI3KCA mutation and PTEN loss in response to AKT inhibition, we tested the antitumor activity of AZD5363 in two patient-derived GC xenograft (PDGCX) models harboring either PI3KCA mutation or PTEN loss. Our data indicated that AZD5363 monotherapy treatment led to a moderate response in the PI3KCA mutant PDGCX model. Whilst monotherapy AZD5363 or Taxotere were ineffective in the PTEN negative PDGCX model, significant anti-tumor activity was observed when AZD5363 was combined with Taxotere.Our results indicated that PI3KCA mutation is an important determinant of response to AKT inhibition in GC and combination with AZD5363 can overcome innate resistance to Taxotere in a PTEN loss PDGCX model. It is suggested that AKT inhibitor is an attractive option for treatment of a new segment of GC patients with aberrant PI3K/AKT signaling.

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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
Drug Name Trade Name Synonyms Drug Classes Drug Description
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
PIK3CA H1047R stomach cancer sensitive Capivasertib Preclinical - Pdx Actionable In a preclinical study, AZD5363 inhibited growth in a patient-derived xenograft model of gastric cancer harboring a PIK3CA H1047R mutation (PMID: 24088382). 24088382
PIK3CA E545K gastrointestinal system cancer sensitive Capivasertib Preclinical Actionable In a preclinical study, gastric cancer cells harboring PI3KCA E545K mutations were sensitive to the AKT inhibitor AZD5363 (PMID: 24088382). 24088382
PIK3CA E542K gastrointestinal system cancer sensitive Capivasertib Preclinical Actionable In a preclinical study, gastric cancer cells harboring PI3KCA E542K mutations were sensitive to the AKT inhibitor AZD5363 (PMID: 24088382). 24088382