Abstract 4266: DNA Repair Enzyme Signature as a new strategy to stratify patients in metastatic melanoma

Abstract

Abstract Metastatic melanoma is an aggressive malignancy with a median survival of less than 1 year. Recent progresses have permitted the discovery of several activating mutations in the MAPK pathway that involves notably the BRAF and NRAS genes and have allowed the development of new targeted therapies. However response to these therapies is highly variable and the occurrence of new activating mutations refrain these progresses. Indeed investigation of the molecular profile of the tumors could help anticipate the occurrence of resistance. However given the multiplicity of redundant kinase pathways this strategy is hardly implementable today. Consequently the identification of other predictive biomarkers is of critical importance. DNA repair, a set of highly coordinated mechanisms, are the effectors of the DNA Damage Response (DDR). They are under the regulation of numerous transduction pathways (PIK3CA, MAPK, etc). Because of this downstream position, we aimed at investigating if the stratification of metastatic melanoma cells, based on the comparative quantification of multiple DNA Repair pathways (DNA Repair Enzyme Signature) reflected the functionality of the signaling pathways. For this purpose, we screened a biobank constituted by a set of 44 samples prepared from metastatic melanoma lymph nodes, dissociated and frozen right after surgery. Nuclear extracts were prepared from the cryopreserved cells. We then used a multiplexed Enzymatic DNA Excision/Synthesis Repair Assay on biochip to simultaneously quantify several DNA Repair pathways (Nucleotide and Base Excision Repair, Inter-Strand Cross-Link Repair). We thus obtained a specific and comprehensive overview of the DNA Repair capacities. Using the normalized data and hierarchical classification, patients were stratified into 3 significantly different main classes. Mutational status (BRAF V600E, NRAS Q61K and NRAS Q61R mutations) was available for most samples. We found out that 6 out of the 7 NRAS mutated samples were clustered in the same group and that 8 out of the 12 BRAF mutated samples were clustered in another group. Two BRAF mutated samples were atypical and clustered alone. Our results suggested that some mutations in the regulating signaling pathway impacted the DDR and were associated with specific DNA Repair Enzyme Signatures. However further studies are needed to more deeply examine if specific combination of DNA Repair-related parameters could serve as surrogate biomarker of signal transduction pathway functionality and could have a predictive value regarding the response to therapy. Citation Format: Sylvie Sauvaigo, Fanny Sarrazy, Florence de Fraipont, Julie Guy, Marie-Thérèse Leccia. DNA Repair Enzyme Signature as a new strategy to stratify patients in metastatic melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4266. doi:10.1158/1538-7445.AM2015-4266