Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer.

Abstract

The mechanistic target of rapamycin (mTOR) is a rational target for cancer treatment. While the mTORC1-selective rapalogs have shown significant benefits in the clinic, antitumor response may be further improved by inhibiting both mTORC1 and mTORC2. Herein, we established target profile of a novel mTOR kinase inhibitor (mTOR-KI) MTI-31 and employed it to study new therapeutic mechanism in breast cancer. MTI-31 demonstrated a potent mTOR binding affinity with >5000 fold selectivity over the related PI3K family isoforms. MTI-31 inhibited mTORC1- and mTORC2 function at ≤120 nM in cellular assays or 5 mg/kg orally in tumor-bearing mice. In a panel of breast cancer lines, the antitumor efficacy of MTI-31 was dependent on HER2+ and/or PIK3CAmut (HER2+/PIK3CAmut) status of the tumors and required mTORC2-specific modulation of Bim, MCL-1 and GSK3. Inactivation of Bim or GSK3 each attenuated apoptotic death resulting in mTOR-KI resistance. The antitumor response also required a suppression of lipid metabolism in therapy-sensitive tumors. Treatment with MTI-31 or AZD8055 substantially reduced lipogenesis and acetyl-CoA homeostasis, which was mechanistically linked to a blockade of mTORC2-dependent glucose-to-lipid conversion rate. We also found that the basal levels of carnitine palmitoyltransferase 1A and lipid catabolism were elevated in HER2+/PIK3CAmut breast cells and were inhibited upon mTOR-KI treatment. A CPT1A inhibitor etomoxir mimicked MTI-31 action in selective downregulation of cellular lipid catabolism. Co-treatments with MTI-31 and etomoxir enhanced the suppression of cyclin D1, c-Myc and cell growth in HER2+/PIK3CAmut tumors. These new mechanistic findings provide a rationale for targeting mTORC1 and mTORC2 in HER2+/PIK3CAmut breast cancer.

• Authors: Jianchang Qian, Yaqing Chen, Tao Meng, Lanping Ma, Lanfang Meng, Xin Wang, Ting Yu, Arie Zask, Jingkang Shen, Ker Yu
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 41 Pg. 67071-67086 (Oct 11 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27563814 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• MTOR protein, human
• Class I Phosphatidylinositol 3-Kinases
• PIK3CA protein, human
• ERBB2 protein, human
• Receptor, ErbB-2
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• TOR Serine-Threonine Kinases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Proliferation (drug effects)
• Class I Phosphatidylinositol 3-Kinases (genetics)
• Female
• Humans
• Lipid Metabolism (drug effects)
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors)
• Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Protein Kinase Inhibitors (pharmacology)
• Receptor, ErbB-2 (genetics)
• TOR Serine-Threonine Kinases (antagonists & inhibitors)
• Xenograft Model Antitumor Assays