Beyond Rapalog Therapy: Preclinical Pharmacology and Antitumor Activity of WYE-125132, an ATP-Competitive and Specific Inhibitor of mTORC1 and mTORC2

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 2; pp. 621 - 631
• Main Authors: KER YU, SHI, Celine, SUNG KYOO KIM, CONANT, Roger, CURRAN, Kevin, KAPLAN, Joshua, VERHEIJEN, Jeroen, AYRAL-KALOUSTIAN, Semiramis, MANSOUR, Tarek S, ABRAHAM, Robert T, ZASK, Arie, GIBBONS, James J, TORAL-BARZA, Lourdes, LUCAS, Judy, SHOR, Boris, JAE EUN KIM, ZHANG, Wei-Guo, MAHONEY, Robert, GAYDOS, Christine, TARDIO, Luanna
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.01.2010
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Cycle - drug effects; Cell Growth Processes - drug effects; Cell Hypoxia - drug effects; Female; Humans; Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; Intracellular Signaling Peptides and Proteins - metabolism; Mechanistic Target of Rapamycin Complex 1; Medical sciences; Mice; Multiprotein Complexes; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Pharmacology. Drug treatments; Phenylurea Compounds - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Pyrazoles - pharmacology; Sirolimus - analogs & derivatives; TOR Serine-Threonine Kinases; Transcription Factors - antagonists & inhibitors; Tumors; Antineoplastic agent; Competition; Treatment; Preclinical trial; Inhibitor; Pharmacology; ATP; Biological activity
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-2340

The mammalian target of rapamycin (mTOR) is a major component of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway that is dysregulated in 50% of all human malignancies. Rapamycin and its analogues (rapalogs) partially inhibit mTOR through allosteric binding to mTOR complex 1 (mTORC1) but not mTOR complex 2 (mTORC2), an emerging player in cancer. Here, we report WYE-125132 (WYE-132), a highly potent, ATP-competitive, and specific mTOR kinase inhibitor (IC(50): 0.19 +/- 0.07 nmol/L; >5,000-fold selective versus PI3Ks). WYE-132 inhibited mTORC1 and mTORC2 in diverse cancer models in vitro and in vivo. Importantly, consistent with genetic ablation of mTORC2, WYE-132 targeted P-AKT(S473) and AKT function without significantly reducing the steady-state level of the PI3K/PDK1 activity biomarker P-AKT(T308), highlighting a prominent and direct regulation of AKT by mTORC2 in cancer cells. Compared with the rapalog temsirolimus/CCI-779, WYE-132 elicited a substantially stronger inhibition of cancer cell growth and survival, protein synthesis, cell size, bioenergetic metabolism, and adaptation to hypoxia. Oral administration of WYE-132 to tumor-bearing mice showed potent single-agent antitumor activity against MDA361 breast, U87MG glioma, A549 and H1975 lung, as well as A498 and 786-O renal tumors. An optimal dose of WYE-132 achieved a substantial regression of MDA361 and A549 large tumors and caused complete regression of A498 large tumors when coadministered with bevacizumab. Our results further validate mTOR as a critical driver for tumor growth, establish WYE-132 as a potent and profound anticancer agent, and provide a strong rationale for clinical development of specific mTOR kinase inhibitors as new cancer therapy.