Fumarate hydratase as a therapeutic target in renal cancer

ABSTRACT

Introduction

Renal cell carcinoma (RCC) is a heterogeneous group of cancers that can occur sporadically or as a manifestation of various inherited syndromes. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is one such inherited syndrome that predisposes patients to HLRCC-associated RCC. These tumors are notoriously aggressive and often exhibit early metastases. HLRCC results from germline mutations in the FH gene, which encodes the citric acid cycle enzyme fumarate hydratase (FH). FH loss leads to alterations in oxidative carbon metabolism, necessitating a switch to aerobic glycolysis, as well as a pseudohypoxic response and consequent upregulation of various pro-survival pathways. Mutations in FH also alter tumor cell migratory potential, response to oxidative stress, and response to DNA damage.

Areas covered

We review the mechanisms by which FH loss leads to HLRCC-associated RCC and how these mechanisms are being rationally targeted.

Expert opinion

FH loss results in the activation of numerous salvage pathways for tumor cell survival in HLRCC-associated RCC. Tumor heterogeneity requires individualized characterization via next-generation sequencing, ultimately resulting in HLRCC-specific treatment regimens. As HLRCC-associated RCC represents a classic Warburg tumor, targeting aerobic glycolysis is particularly promising as a future therapeutic avenue.

KEYWORDS:

• Fumarate hydratase
• FH
• renal cell carcinoma
• hereditary leiomyomatosis and renal cell carcinoma
• HLRCC

Acknowledgments

The authors are grateful to their colleagues, Drs W. Marston Linehan, Ramaprasad Srinivasan, Laura S. Schmidt, Don Bottaro, and Len Neckers for their stimulating discussions.

Article highlights

• Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma is a distinct histologic subtype of renal cell carcinoma with an aggressive disease course and limited treatment options.

• HLRCC is the result of germline mutations in the citric acid cycle enzyme fumarate hydratase (FH). Loss of FH function is associated with metabolic dysregulation leading to cell survival through aerobic glycolysis and a pseudohypoxia response.

• FH loss is also implicated in epithelial to mesenchymal transition, epigenetic modification, and impaired DNA damage repair. These are pro-oncogenic processes that can be targeted for therapeutic benefit.

• Promising clinical trials include targeting HIF targets to mitigate the pseudohypoxic drive, inhibiting glycolysis, and regulating reactive oxygen species. Targeting glycolysis via lactate dehydrogenase A inhibition is a particularly exciting direction for future research.

• In the future, molecular characterization of HLRCC tumors via next-generation sequencing will identify individualized therapeutic targets to improve clinical outcomes.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was partly supported by the Department of Defense (KC190038 to M.M.) and National Institute of General Medical Sciences of the NIH (R01 GM124256 to M.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported by funds from SUNY Upstate Medical University, the Upstate Foundation, and the Upstate Cancer Center (M.M.).