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

Abstract

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.

• Authors: Robert Mallon, Irwin Hollander, Larry Feldberg, Judy Lucas, Veronica Soloveva, Aranapakam Venkatesan, Christoph Dehnhardt, Efren Delos Santos, Zecheng Chen, Osvaldo Dos Santos, Semiramis Ayral-Kaloustian, Jay Gibbons
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 9 Issue 4 Pg. 976-84 (Apr 2010) ISSN: 1538-8514 [Electronic] United States
• PMID: 20371716 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Forkhead Transcription Factors
• Intracellular Signaling Peptides and Proteins
• PKI 402
• Phenylurea Compounds
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyrimidines
• Green Fluorescent Proteins
• Poly(ADP-ribose) Polymerases
• MTOR protein, human
• mTOR protein, mouse
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Caspases

Topics

• Animals
• Biomarkers, Tumor (metabolism)
• Caspases (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Enzyme Assays
• Forkhead Transcription Factors (metabolism)
• Green Fluorescent Proteins (metabolism)
• Humans
• Inhibitory Concentration 50
• Intracellular Signaling Peptides and Proteins (antagonists & inhibitors)
• Mice
• Phenylurea Compounds (blood, chemistry, pharmacology)
• Phosphoinositide-3 Kinase Inhibitors
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Kinase Inhibitors (blood, chemistry, pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (blood, chemistry, pharmacology)
• TOR Serine-Threonine Kinases
• Xenograft Model Antitumor Assays