Abstract 2177: Roles of lactate dehydrogenase (LDH) in melanoma: an underestimated prognostic biomarker

Abstract

Abstract Introduction: High LDH activity is associated with a poor prognosis in many cancer types, especially in melanoma where it is the strongest indicator of poor outcome even with the most potent anticancer immunotherapies or targeted therapies. Although high LDH blood activity is often associated with high tumor burden, this is not always the case and there is no definitive demonstration that blood LDH activity is directly derived from tumors cells. Our objectives were 1) to explore the biological impact of LDHA and LDHB independently of their metabolic function 2) to explore the respective prognostic values of the 5 LDH isoforms as well as the relationship between tumor and blood LDH isoforms repartition in melanoma patients. Material, Patients, Methods: A375 melanoma cells cultured in glucose or galactose (to evaluate glycolytic independent effects) were silenced for LDHA or LDHB expression using si-RNAs. RNAseq analysis of total RNAs and polysomal RNAs was performed to explore the transcriptional and translational impacts of LDHA and LDHB expression. In melanoma patients treated with immunotherapy, the enzymatic activities of each of the 5 LDH isoforms (encoded by LDHA and LDHB) were measured in tumors and blood samples. The prognostic values of the distinct isoforms as well as the correlation between the isoforms distribution in blood and tumors were evaluated. Results: In vitro, independently of their metabolic effect, both LDHA and LDHB had distinct transcriptional and translational impacts on the control of several key oncogenic pathways (adhesion, survival, proliferation, immunity) with a more important effect of LDHA vs LDHB silencing. In vivo, among 64 melanoma patients including 25% with high LDH, high LDH1 (B4) activity was significantly associated with response and overall survival (OS) whereas high LDH4 (A3B1) was inversely associated with response and OS. LDH1 and LDH4 were associated with survival even among patients with normal LDH levels. For patients with paired (tumor and blood) isoforms analysis, there was no correlation between isoforms repartition suggesting that blood LDH activity is not directly related to tumor LDH. Conclusion: In addition to their metabolic activity, LDH enzymes, particularly LDHA, control several key oncogenic pathways at the transcriptional level but also at the translational level for a set of genes involved in cancer biology. LDH1 and LDH4 isoforms blood levels are differentially correlated with response to immunotherapy and survival. They are more robust prognostic biomarkers than total blood LDH level used in our daily practice. Thus, LDH is much more than just a marker of tumor burden in melanoma and the origins, the significance and the roles of blood LDH isoforms need to be revisited. These results highlight the need to develop anticancer drugs targeting LDH, and especially LDHA. Citation Format: Laura Soumoy, Virginie Quidville, Lisa Fredeau, Giuseppina Claps, Caroline Pradon, Ludovic Lacroix, Emilie Routier, Djaouida Belkadi, Séverine Roy, Feras Chehade, Stephan Vagner, Caroline Robert. Roles of lactate dehydrogenase (LDH) in melanoma: an underestimated prognostic biomarker [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2177.