Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir−bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death

Johnson, Charlotte E. ORCID: https://orcid.org/0000-0003-1954-5142, Dunlop, Elaine A. ORCID: https://orcid.org/0000-0002-9209-7561, Seifan, Sara, McCann, Henry D., Hay, Trevor, Parfitt, Geraint J. ORCID: https://orcid.org/0000-0002-8704-7906, Jones, Ashley T., Giles, Peter J. ORCID: https://orcid.org/0000-0003-3143-6854, Shen, Ming H. ORCID: https://orcid.org/0000-0002-3891-7231, Sampson, Julian R. ORCID: https://orcid.org/0000-0002-2902-2348, Errington, Rachel J. ORCID: https://orcid.org/0000-0002-8016-4376, Davies, D. Mark and Tee, Andrew R. ORCID: https://orcid.org/0000-0002-5577-4631 2018. Loss of tuberous sclerosis complex 2 sensitizes tumors to nelfinavir−bortezomib therapy to intensify endoplasmic reticulum stress-induced cell death. Oncogene 37 , pp. 5913-5925. 10.1038/s41388-018-0381-2

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Abstract

Cancer cells lose homeostatic flexibility because of mutations and dysregulated signaling pathways involved in maintaining homeostasis. Tuberous Sclerosis Complex 1 (TSC1) and TSC2 play a fundamental role in cell homeostasis, where signal transduction through TSC1/TSC2 is often compromised in cancer, leading to aberrant activation of mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 hyperactivation increases the basal level of endoplasmic reticulum (ER) stress via an accumulation of unfolded protein, due to heightened de novo protein translation and repression of autophagy. We exploit this intrinsic vulnerability of tumor cells lacking TSC2, by treating with nelvinavir to further enhance ER stress while inhibiting the proteasome with bortezomib to prevent effective protein removal. We show that TSC2-deficient cells are highly dependent on the proteosomal degradation pathway for survival. Combined treatment with nelfinavir and bortezomib at clinically relevant drug concentrations show synergy in selectively killing TSC2-deficient cells with limited toxicity in control cells. This drug combination inhibited tumor formation in xenograft mouse models and patient-derived cell models of TSC and caused tumor spheroid death in 3D culture. Importantly, 3D culture assays differentiated between the cytostatic effects of the mTORC1 inhibitor, rapamycin, and the cytotoxic effects of the nelfinavir/bortezomib combination. Through RNA sequencing, we determined that nelfinavir and bortezomib tip the balance of ER protein homeostasis of the already ER-stressed TSC2-deficient cells in favor of cell death. These findings have clinical relevance in stratified medicine to treat tumors that have compromised signaling through TSC and are inflexible in their capacity to restore ER homeostasis.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Medicine Biosciences
Publisher:	Springer Nature
ISSN:	0950-9232
Date of First Compliant Deposit:	26 July 2018
Date of Acceptance:	31 May 2018
Last Modified:	06 Nov 2024 19:45
URI:	https://orca.cardiff.ac.uk/id/eprint/113463

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