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Energy stress-mediated cytotoxicity in tuberous sclerosis complex 2-deficient cells with nelfinavir and mefloquine treatment

McCann, Henry, Johnson, Charlotte ORCID:, Errington, Rachel ORCID:, Davies, D. Mark, Dunlop, Elaine ORCID: and Tee, Andrew ORCID: 2018. Energy stress-mediated cytotoxicity in tuberous sclerosis complex 2-deficient cells with nelfinavir and mefloquine treatment. Cancers 10 (10) , -. 10.3390/cancers10100375

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Advanced Research Computing @ Cardiff (ARCCA)
Publisher: MDPI
ISSN: 2072-6694
Date of First Compliant Deposit: 12 October 2018
Date of Acceptance: 3 October 2018
Last Modified: 04 May 2023 21:45

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