Reference Detail

Ref Type

Journal Article

PMID

(20371716)

Authors

Mallon R, Hollander I, Feldberg L, Lucas J, Soloveva V, Venkatesan A, Dehnhardt C, Delos Santos E, Chen Z, Dos Santos O, Ayral-Kaloustian S, Gibbons J

Title

Antitumor efficacy profile of PKI-402, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	9	4	2010 Apr	976-84	Mol Cancer Ther

URL

Abstract Text

PKI-402 is a selective, reversible, ATP-competitive, equipotent inhibitor of class I phosphatidylinositol 3-kinases (PI3K), including PI3K-alpha mutants, and mammalian target of rapamycin (mTOR; IC(50) versus PI3K-alpha = 2 nmol/L). PKI-402 inhibited growth of human tumor cell lines derived from breast, brain (glioma), pancreas, and non-small cell lung cancer tissue and suppressed phosphorylation of PI3K and mTOR effector proteins (e.g., Akt at T308) at concentrations that matched those that inhibited cell growth. In MDA-MB-361 [breast: Her2(+) and PIK3CA mutant (E545K)], 30 nmol/L PKI-402 induced cleaved poly(ADP-ribose) polymerase (PARP), a marker for apoptosis. In vivo, PKI-402 inhibited tumor growth in MDA-MB-361, glioma (U87MG), and lung (A549) xenograft models. In MDA-MB-361, PKI-402 at 100 mg/kg (daily for 5 days, one round) reduced initial tumor volume of 260 mm(3) to 129 mm(3) and prevented tumor regrowth for 70 days. In MDA-MB-361 tumors, PKI-402 (100 mg/kg, single dose) suppressed Akt phosphorylation (at T308) and induced cleaved PARP. Suppression of phosphorylated Akt (p-Akt) was complete at 8 hours and still evident at 24 hours. Cleaved PARP was evident at 8 and 24 hours. In normal tissue (heart and lung), PKI-402 (100 mg/kg) had minimal effect on p-Akt, with no detectable cleaved PARP. Preferential accumulation of PKI-402 in tumor tissue was observed. Complete, sustained suppression of Akt phosphorylation may cause tumor regression in MDA-MB-361 and other xenograft models. We are testing whether dual PI3K/mTOR inhibitors can durably suppress p-Akt, induce cleaved PARP, and cause tumor regression in a diverse set of human tumor xenograft models. Mol Cancer Ther; 9(4); 976-84. (c)2010 AACR.

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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
PKI-402	PKI-402	2	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
PKI-402			mTOR Inhibitor 51 PI3K Inhibitor (Pan) 42	PKI-402 is a dual ATP-competitive mTOR/PI3K inhibitor, which leads to reduced downstream signaling, potentially resulting in decreased tumor growth (PMID: 20371716, PMID: 32585451).

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 loss	glioblastoma	sensitive	PKI-402	Preclinical - Cell line xenograft	Actionable	In a preclinical study, PKI-402 inhibited tumor growth in PTEN-negative glioblastoma multiforme cell line xenograft models (PMID: 20371716).	20371716
PIK3CA E545K	breast cancer	sensitive	PKI-402	Preclinical - Cell line xenograft	Actionable	In a preclinical study, treatment with PKI-402 resulted in decreased Akt phosphorylation and tumor regression in ERBB2 (HER2)-positive breast cancer cell line xenograft models harboring PIK3CA E545K (PMID: 20371716).	20371716