Reference Detail

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	Vol	Issue	Date	Pages	Journal Short Title
Journal of translational medicine	11		2013 Oct 02	241	J Transl Med

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 E542K	gastrointestinal system cancer	sensitive	Capivasertib	Preclinical - Cell culture	Actionable	In a preclinical study, gastric cancer cells harboring PIK3CA E542K demonstrated sensitivity to the AKT inhibitor Truqap (capivasertib), resulting in decreased proliferation in culture (PMID: 24088382).	24088382
PIK3CA E545K	gastrointestinal system cancer	sensitive	Capivasertib	Preclinical - Cell culture	Actionable	In a preclinical study, gastric cancer cells harboring PIK3CA E545K demonstrated sensitivity to the AKT inhibitor Truqap (capivasertib), resulting in decreased proliferation in culture (PMID: 24088382).	24088382
PIK3CA H1047R	stomach cancer	sensitive	Capivasertib	Preclinical - Pdx	Actionable	In a preclinical study, Truqap (capivasertib) inhibited growth in a patient-derived xenograft model of gastric cancer harboring a PIK3CA H1047R mutation (PMID: 24088382).	24088382