The TORC1/2 inhibitor TAK228 sensitizes atypical teratoid rhabdoid tumors to cisplatin-induced cytotoxicity.

Abstract

BACKGROUND:

Atypical teratoid/rhabdoid tumors (AT/RTs) are deadly pediatric brain tumors driven by LIN28. Mammalian target of rapamycin (mTOR) is activated in many deadly, drug-resistant cancers and governs important cellular functions such as metabolism and survival. LIN28 regulates mTOR in normal cells. We therefore hypothesized that mTOR is activated downstream of LIN28 in AT/RT, and the brain-penetrating mTOR complex 1 and 2 (mTORC1/2) kinase inhibitor TAK228 would reduce AT/RT tumorigenicity.

METHODS:

Activation of mTOR in AT/RT was determined by measuring pS6 and pAKT (Ser473) by immunohistochemistry on tissue microarray of 18 primary AT/RT tumors. In vitro growth assays (BrdU and MTS), death assays (CC3, c-PARP by western blot), and survival curves of AT/RT orthotopic xenograft models were used to measure the efficacy of TAK228 alone and in combination with cisplatin.

RESULTS:

Lentiviral short hairpin RNA-mediated knockdown of LIN28A led to decreased mTOR activation. Primary human AT/RT had high levels of pS6 and pAKT (Ser473) in 21% and 87% of tumors by immunohistochemistry. TAK228 slowed cell growth, induced apoptosis in vitro, and nearly doubled median survival of orthotopic xenograft models of AT/RT. TAK228 combined with cisplatin synergistically slowed cell growth and enhanced cisplatin-induced apoptosis. Suppression of AKT sensitized cells to cisplatin-induced apoptosis and forced activation of AKT protected cells. Combined treatment with TAK228 and cisplatin significantly extended survival of orthotopic xenograft models of AT/RT compared with each drug alone.

CONCLUSIONS:

TAK228 has efficacy in AT/RT as a single agent and synergizes with conventional chemotherapies by sensitizing tumors to cisplatin-induced apoptosis. These results suggest TAK228 may be an effective new treatment for AT/RT.

• Authors: Jeffrey A Rubens, Sabrina Z Wang, Antoinette Price, Melanie F Weingart, Sariah J Allen, Brent A Orr, Charles G Eberhart, Eric H Raabe
• Journal: Neuro-oncology (Neuro Oncol) Vol. 19 Issue 10 Pg. 1361-1371 (Oct 01 2017) ISSN: 1523-5866 [Electronic] England
• PMID: 28582547 (Publication Type: Journal Article)
• Copyright: © The Author(s) 2017. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: [email protected]

Chemical References

• Antineoplastic Agents
• Benzoxazoles
• Protein Kinase Inhibitors
• Pyrimidines
• MTOR protein, human
• TOR Serine-Threonine Kinases
• sapanisertib
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Apoptosis (drug effects)
• Benzoxazoles (pharmacology)
• Brain Neoplasms (drug therapy)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Humans
• Mice
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Rhabdoid Tumor (drug therapy)
• TOR Serine-Threonine Kinases (drug effects)
• Teratoma (drug therapy)
• Xenograft Model Antitumor Assays (methods)