Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors

Authors

Gao Zhang, The Wistar Institute
Dennie T. Frederick, Massachusetts General Hospital Cancer Center
Lawrence Wu, The Wistar Institute
Zhi Wei, Department of Computer Science
Clemens Krepler, The Wistar Institute
Satish Srinivasan, University of Pennsylvania
Young Chan Chae, The Wistar Institute
Xiaowei Xu, Hospital of the University of Pennsylvania
Harry Choi, The Wistar Institute
Elaida Dimwamwa, The Wistar Institute
Omotayo Ope, The Wistar Institute
Batool Shannan, The Wistar Institute
Devraj Basu, University of Pennsylvania Perelman School of Medicine
Dongmei Zhang, University of Pennsylvania Perelman School of Medicine
Manti Guha, University of Pennsylvania
Min Xiao, The Wistar Institute
Sergio Randell, The Wistar Institute
Katrin Sproesser, The Wistar Institute

Document Type

Article

Publication Date

5-2-2016

Abstract

Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAF^V600E 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.

Identifier

84988531155 (Scopus)

Publication Title

Journal of Clinical Investigation

External Full Text Location

https://doi.org/10.1172/JCI82661

e-ISSN

15588238

ISSN

00219738

PubMed ID

27043285

First Page

1834

Last Page

1856

Issue

5

Volume

126

Grant

CA010815

Fund Ref

National Institutes of Health

Recommended Citation

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; and Sproesser, Katrin, "Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors" (2016). Faculty Publications. 10541.
https://digitalcommons.njit.edu/fac_pubs/10541