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

• Published in: Neuro-oncology (Charlottesville, Va.) Va.), 2017-10, Vol.19 (10), p.1361-1371
• Main Authors: Rubens, Jeffrey A, Wang, Sabrina Z, Price, Antoinette, Weingart, Melanie F, Allen, Sariah J, Orr, Brent A, Eberhart, Charles G, Raabe, Eric H
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - therapeutic use; Apoptosis - drug effects; Basic and Translational Investigations; 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; Teratoma - drug therapy; TOR Serine-Threonine Kinases - drug effects; Xenograft Model Antitumor Assays - methods
• ISSN: 1522-8517; 1523-5866
• DOI: 10.1093/neuonc/nox067

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. 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. 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. 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.