Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors

Gao Zhang, Dennie T. Frederick, Lawrence Wu, Zhi Wei, Clemens Krepler, Satish Srinivasan, Young Chan Chae, Xiaowei Xu, Harry Choi, Elaida Dimwamwa, Omotayo Ope, Batool Shannan, Devraj Basu, Dongmei Zhang, Manti Guha, Min Xiao, Sergio Randell, Katrin Sproesser, Wei Xu, Jephrey LiuGiorgos C. Karakousis, Lynn M. Schuchter, Tara C. Gangadhar, Ravi K. Amaravadi, Mengnan Gu, Caiyue Xu, Abheek Ghosh, Weiting Xu, Tian Tian, Jie Zhang, Shijie Zha, Qin Liu, Patricia Brafford, Ashani Weeraratna, Michael A. Davies, Jennifer A. Wargo, Narayan G. Avadhani, Yiling Lu, Gordon Mills, Dario C. Altieri, Keith T. Flaherty, Meenhard Herlyn

Research output: Contribution to journalArticle

72 Citations (Scopus)

Abstract

Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi.

Original languageEnglish (US)
Pages (from-to)1834-1856
Number of pages23
JournalJournal of Clinical Investigation
Volume126
Issue number5
DOIs
StatePublished - May 2 2016
Externally publishedYes

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Organelle Biogenesis
Drug Resistance
Energy Metabolism
Melanoma
Neoplasms
Mitochondrial Genome
Mitochondrial Proteins
Oxidative Phosphorylation
Protein Folding
Mitochondrial DNA
Disease Progression
Biopsy
Cell Line
Survival
Therapeutics
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zhang, G., Frederick, D. T., Wu, L., Wei, Z., Krepler, C., Srinivasan, S., ... Herlyn, M. (2016). Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. Journal of Clinical Investigation, 126(5), 1834-1856. https://doi.org/10.1172/JCI82661

Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. / Zhang, Gao; Frederick, Dennie T.; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Ope, Omotayo; Shannan, Batool; Basu, Devraj; Zhang, Dongmei; Guha, Manti; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Wei; Liu, Jephrey; Karakousis, Giorgos C.; Schuchter, Lynn M.; Gangadhar, Tara C.; Amaravadi, Ravi K.; Gu, Mengnan; Xu, Caiyue; Ghosh, Abheek; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie; Liu, Qin; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A.; Wargo, Jennifer A.; Avadhani, Narayan G.; Lu, Yiling; Mills, Gordon; Altieri, Dario C.; Flaherty, Keith T.; Herlyn, Meenhard.

In: Journal of Clinical Investigation, Vol. 126, No. 5, 02.05.2016, p. 1834-1856.

Research output: Contribution to journalArticle

Zhang, G, Frederick, DT, Wu, L, Wei, Z, Krepler, C, Srinivasan, S, Chae, YC, Xu, X, Choi, H, Dimwamwa, E, Ope, O, Shannan, B, Basu, D, Zhang, D, Guha, M, Xiao, M, Randell, S, Sproesser, K, Xu, W, Liu, J, Karakousis, GC, Schuchter, LM, Gangadhar, TC, Amaravadi, RK, Gu, M, Xu, C, Ghosh, A, Xu, W, Tian, T, Zhang, J, Zha, S, Liu, Q, Brafford, P, Weeraratna, A, Davies, MA, Wargo, JA, Avadhani, NG, Lu, Y, Mills, G, Altieri, DC, Flaherty, KT & Herlyn, M 2016, 'Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors', Journal of Clinical Investigation, vol. 126, no. 5, pp. 1834-1856. https://doi.org/10.1172/JCI82661
Zhang G, Frederick DT, Wu L, Wei Z, Krepler C, Srinivasan S et al. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. Journal of Clinical Investigation. 2016 May 2;126(5):1834-1856. https://doi.org/10.1172/JCI82661
Zhang, Gao ; Frederick, Dennie T. ; Wu, Lawrence ; Wei, Zhi ; Krepler, Clemens ; Srinivasan, Satish ; Chae, Young Chan ; Xu, Xiaowei ; Choi, Harry ; Dimwamwa, Elaida ; Ope, Omotayo ; Shannan, Batool ; Basu, Devraj ; Zhang, Dongmei ; Guha, Manti ; Xiao, Min ; Randell, Sergio ; Sproesser, Katrin ; Xu, Wei ; Liu, Jephrey ; Karakousis, Giorgos C. ; Schuchter, Lynn M. ; Gangadhar, Tara C. ; Amaravadi, Ravi K. ; Gu, Mengnan ; Xu, Caiyue ; Ghosh, Abheek ; Xu, Weiting ; Tian, Tian ; Zhang, Jie ; Zha, Shijie ; Liu, Qin ; Brafford, Patricia ; Weeraratna, Ashani ; Davies, Michael A. ; Wargo, Jennifer A. ; Avadhani, Narayan G. ; Lu, Yiling ; Mills, Gordon ; Altieri, Dario C. ; Flaherty, Keith T. ; Herlyn, Meenhard. / Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 5. pp. 1834-1856.
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abstract = "Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi.",
author = "Gao Zhang and Frederick, {Dennie T.} and Lawrence Wu and Zhi Wei and Clemens Krepler and Satish Srinivasan and Chae, {Young Chan} and Xiaowei Xu and Harry Choi and Elaida Dimwamwa and Omotayo Ope and Batool Shannan and Devraj Basu and Dongmei Zhang and Manti Guha and Min Xiao and Sergio Randell and Katrin Sproesser and Wei Xu and Jephrey Liu and Karakousis, {Giorgos C.} and Schuchter, {Lynn M.} and Gangadhar, {Tara C.} and Amaravadi, {Ravi K.} and Mengnan Gu and Caiyue Xu and Abheek Ghosh and Weiting Xu and Tian Tian and Jie Zhang and Shijie Zha and Qin Liu and Patricia Brafford and Ashani Weeraratna and Davies, {Michael A.} and Wargo, {Jennifer A.} and Avadhani, {Narayan G.} and Yiling Lu and Gordon Mills and Altieri, {Dario C.} and Flaherty, {Keith T.} and Meenhard Herlyn",
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AU - Frederick, Dennie T.

AU - Wu, Lawrence

AU - Wei, Zhi

AU - Krepler, Clemens

AU - Srinivasan, Satish

AU - Chae, Young Chan

AU - Xu, Xiaowei

AU - Choi, Harry

AU - Dimwamwa, Elaida

AU - Ope, Omotayo

AU - Shannan, Batool

AU - Basu, Devraj

AU - Zhang, Dongmei

AU - Guha, Manti

AU - Xiao, Min

AU - Randell, Sergio

AU - Sproesser, Katrin

AU - Xu, Wei

AU - Liu, Jephrey

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AU - Schuchter, Lynn M.

AU - Gangadhar, Tara C.

AU - Amaravadi, Ravi K.

AU - Gu, Mengnan

AU - Xu, Caiyue

AU - Ghosh, Abheek

AU - Xu, Weiting

AU - Tian, Tian

AU - Zhang, Jie

AU - Zha, Shijie

AU - Liu, Qin

AU - Brafford, Patricia

AU - Weeraratna, Ashani

AU - Davies, Michael A.

AU - Wargo, Jennifer A.

AU - Avadhani, Narayan G.

AU - Lu, Yiling

AU - Mills, Gordon

AU - Altieri, Dario C.

AU - Flaherty, Keith T.

AU - Herlyn, Meenhard

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