GCN2 eIF2 kinase promotes prostate cancer by maintaining amino acid homeostasis
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Evaluation Summary:
This manuscript is an important body of work that addresses the role of the integrated stress response (ISR) and the role of the GCN2 protein kinase in prostate cancer. The studies comprehensively elucidate how GCN2 and amino acid transporters and uptake promote prostate cancer proliferation, as well as the therapeutic potential of inhibiting this pathway. This work, therefore, provides insights for both identification of new mechanisms and experimental therapeutics in prostate cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Abstract
A stress adaptation pathway termed the integrated stress response has been suggested to be active in many cancers including prostate cancer (PCa). Here, we demonstrate that the eIF2 kinase GCN2 is required for sustained growth in androgen-sensitive and castration-resistant models of PCa both in vitro and in vivo, and is active in PCa patient samples. Using RNA-seq transcriptome analysis and a CRISPR-based phenotypic screen, GCN2 was shown to regulate expression of over 60 solute-carrier ( SLC ) genes, including those involved in amino acid transport and loss of GCN2 function reduces amino acid import and levels. Addition of essential amino acids or expression of 4F2 (SLC3A2) partially restored growth following loss of GCN2, suggesting that GCN2 targeting of SLC transporters is required for amino acid homeostasis needed to sustain tumor growth. A small molecule inhibitor of GCN2 showed robust in vivo efficacy in androgen-sensitive and castration-resistant mouse models of PCa, supporting its therapeutic potential for the treatment of PCa.
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Evaluation Summary:
This manuscript is an important body of work that addresses the role of the integrated stress response (ISR) and the role of the GCN2 protein kinase in prostate cancer. The studies comprehensively elucidate how GCN2 and amino acid transporters and uptake promote prostate cancer proliferation, as well as the therapeutic potential of inhibiting this pathway. This work, therefore, provides insights for both identification of new mechanisms and experimental therapeutics in prostate cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The authors provide compelling evidence that the protein kinase GCN2, which is an arm of the integrated stress response (ISR) in cells deprived of amino acids and nutrients, displays a pro-tumorigenic role in prostate cancers.
The strength of the manuscript is its novelty, the well-performed experiments, and the very good quality of data and their analysis. The weak points are focused on a better explanation of the mechanisms of GCN2 function based on the presented data. Minor issues relate to the inclusion of a few control experiments to further improve the quality of the data.
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Reviewer #2 (Public Review):
In this manuscript, Cordova et al. demonstrate using multiple orthogonal models that GCN2 is a therapeutic vulnerability in prostate cancer. In addition, they diligently worked out the mechanism by which GCN2 regulates prostate cancer cell proliferation. This is mediated by transcription regulation of amino acid transporters such as SLC3A2 which impacts the import of essential amino acids such as histidine. Overall, an excellent piece of work.
Strengths - The authors were very careful in their experimentation, making sure observations were repeatable in different prostate cancer cell line models. Furthermore, they conduct knockdown and add back assays to demonstrate the relevance of their mechanistic findings. It was particularly impressive how they reached the conclusion that prostate cancer cell lines …
Reviewer #2 (Public Review):
In this manuscript, Cordova et al. demonstrate using multiple orthogonal models that GCN2 is a therapeutic vulnerability in prostate cancer. In addition, they diligently worked out the mechanism by which GCN2 regulates prostate cancer cell proliferation. This is mediated by transcription regulation of amino acid transporters such as SLC3A2 which impacts the import of essential amino acids such as histidine. Overall, an excellent piece of work.
Strengths - The authors were very careful in their experimentation, making sure observations were repeatable in different prostate cancer cell line models. Furthermore, they conduct knockdown and add back assays to demonstrate the relevance of their mechanistic findings. It was particularly impressive how they reached the conclusion that prostate cancer cell lines require GCN2 regulation of SLC3A2 which impacts amino acid transport and subsequent cell proliferation. In addition to the strong mechanistic findings, they also demonstrate the preclinical relevance of targeting GCN2 in xenograft and PDX models of prostate cancer.
Weaknesses - This is a very well-thought-out and executed set of experiments. The only comment I would add that could strengthen the relevance of this paper is to conduct GCN2 inhibition experiments in normal prostate cell lines (RWPE-1 or BPH1) to determine if the GCN2-SLC3A2-aa axis is uniquely relevant to cancer or not.
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Reviewer #3 (Public Review):
The authors perform a wide range of molecular, cellular tissue, and animal model studies that demonstrate clearly that GCN2 activity impacts amino acid transporter activity and essential amino acid uptake, which is needed for PCa tumor growth in a variety of model systems. As a whole the data are convincing, and the authors have achieved their aims. One potentially translatable finding is that a small molecule inhibitor of GCN2 may be a useful candidate therapeutic tool for certain PCa patients.
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