Abstract | PURPOSE: The aim of this study was to show preclinical efficacy and clinical development potential of PKI-587, a dual phosphoinositide 3-kinase (PI3K)/mTOR inhibitor. EXPERIMENTAL DESIGN: In vitro class 1 PI3K enzyme and human tumor cell growth inhibition assays and in vivo five tumor xenograft models were used to show efficacy. RESULTS: In vitro, PKI-587 potently inhibited class I PI3Ks (IC(50) vs. PI3K-α = 0.4 nmol/L), PI3K-α mutants, and mTOR. PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC(50) values of less than 100 nmol/L. PKI-587 suppressed phosphorylation of PI3K/mTOR effectors (e.g., Akt), and induced apoptosis in human tumor cell lines with elevated PI3K/mTOR signaling. MDA-MB-361 [breast; HER2(+), PIK3CA mutant (E545K)] was particularly sensitive to this effect, with cleaved PARP, an apoptosis marker, induced by 30 nmol/L PKI-587 at 4 hours. In vivo, PKI-587 inhibited tumor growth in breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models. In MDA-MB-361 tumors, PKI-587 (25 mg/kg, single dose i.v.) suppressed Akt phosphorylation [at threonine(T)308 and serine(S)473] for up to 36 hours, with cleaved PARP (cPARP) evident up to 18 hours. PKI-587 at 25 mg/kg (once weekly) shrank large (∼1,000 mm(3)) MDA-MB-361 tumors and suppressed tumor regrowth. Tumor regression correlated with suppression of phosphorylated Akt in the MDA-MB-361 model. PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 ( MEK 1/2 inhibitor), irinotecan ( topoisomerase I inhibitor), or HKI-272 ( neratinib, HER2 inhibitor). CONCLUSION: Significant antitumor efficacy and a favorable pharmacokinetic/safety profile justified phase 1 clinical evaluation of PKI-587.
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Authors | Robert Mallon, Larry R Feldberg, Judy Lucas, Inder Chaudhary, Christoph Dehnhardt, Efren Delos Santos, Zecheng Chen, Osvaldo dos Santos, Semiramis Ayral-Kaloustian, Aranapakam Venkatesan, Irwin Hollander |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 17
Issue 10
Pg. 3193-203
(May 15 2011)
ISSN: 1557-3265 [Electronic] United States |
PMID | 21325073
(Publication Type: Journal Article)
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Copyright | ©2011 AACR. |
Chemical References |
- Antineoplastic Agents
- Morpholines
- Phosphoinositide-3 Kinase Inhibitors
- Protein Kinase Inhibitors
- Triazines
- gedatolisib
- TOR Serine-Threonine Kinases
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Topics |
- Animals
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Cell Line, Tumor
- Female
- HCT116 Cells
- Humans
- Mice
- Mice, Nude
- Morpholines
(pharmacology, therapeutic use)
- Neoplasms
(drug therapy, metabolism)
- Phosphoinositide-3 Kinase Inhibitors
- Protein Kinase Inhibitors
(pharmacology, therapeutic use)
- TOR Serine-Threonine Kinases
(antagonists & inhibitors)
- Treatment Outcome
- Triazines
(pharmacology, therapeutic use)
- Xenograft Model Antitumor Assays
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