4.8 Article

Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors

Journal

JOURNAL OF CLINICAL INVESTIGATION
Volume 126, Issue 5, Pages 1834-1856

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI82661

Keywords

-

Funding

  1. NIH [P01 CA114046, P01 CA025874, P30 CA010815, R01 CA047159]
  2. Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
  3. Melanoma Research Foundation
  4. Cancer Center Support Grant (CCSG) [CA010815]

Ask authors/readers for more resources

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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available