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Cancers 2018, 10(10), 375; https://doi.org/10.3390/cancers10100375

Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment

1
Division of Cancer and Genetics, Cardiff University, Heath Park, Cardiff CF14 4XN, UK
2
Department of Oncology, South West Wales Cancer Centre, Singleton Hospital, Swansea SA2 8QA, UK
*
Author to whom correspondence should be addressed.
Received: 21 August 2018 / Revised: 25 September 2018 / Accepted: 3 October 2018 / Published: 10 October 2018
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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Abstract

To find new anti-cancer drug therapies, we wanted to exploit homeostatic vulnerabilities within Tuberous Sclerosis Complex 2 (TSC2)-deficient cells with mechanistic target of rapamycin complex 1 (mTORC1) hyperactivity. We show that nelfinavir and mefloquine synergize to selectively evoke a cytotoxic response in TSC2-deficient cell lines with mTORC1 hyperactivity. We optimize the concentrations of nelfinavir and mefloquine to a clinically viable range that kill cells that lack TSC2, while wild-type cells tolerate treatment. This new clinically viable drug combination causes a significant level of cell death in TSC2-deficient tumor spheroids. Furthermore, no cell recovery was apparent after drug withdrawal, revealing potent cytotoxicity. Transcriptional profiling by RNA sequencing of drug treated TSC2-deficient cells compared to wild-type cells suggested the cytotoxic mechanism of action, involving initial ER stress and an imbalance in energy homeostatic pathways. Further characterization revealed that supplementation with methyl pyruvate alleviated energy stress and reduced the cytotoxic effect, implicating energy deprivation as the trigger of cell death. This work underpins a critical vulnerability with cancer cells with aberrant signaling through the TSC2-mTORC1 pathway that lack flexibility in homeostatic pathways, which could be exploited with combined nelfinavir and mefloquine treatment. View Full-Text
Keywords: mTOR; nelfinavir; mefloquine; TSC; cancer therapy; energy homeostasis; ER stress mTOR; nelfinavir; mefloquine; TSC; cancer therapy; energy homeostasis; ER stress
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McCann, H.D.; Johnson, C.E.; Errington, R.J.; Davies, D.M.; Dunlop, E.A.; Tee, A.R. Energy Stress-Mediated Cytotoxicity in Tuberous Sclerosis Complex 2-Deficient Cells with Nelfinavir and Mefloquine Treatment. Cancers 2018, 10, 375.

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