Mechanisms of resistance to immuno and targeted therapies in acral melanoma

LEE R, GIROTTI MR, VIROS A, BAENKE F, MANDAL A, KHANDELWAL G, BRIDGEMAN J, GALVANI E, GREMEL G, KALAITSIDOU M, ASHTON A, PESET I, SMITH M, SWAN J, ZENG K, TANG H, ABBEY C, HAWKINS R, FUSI A, MILLER C, GILHAM D, DHOMEN N, LORIGAN P, MARAIS R.

Conferencia; AACR Annual Meeting 2016; 2016

Acral melanoma is a rare subtype of melanoma found on the non-hair bearing surfaces of the skin. It is associated with a worse prognosis than cutaneous melanoma, with higher proportions of patients developing metastatic disease. Combination treatments targeting the MAP kinase (MAPK) pathway and immune checkpoint inhibitors have improved overall survival in patients with stage IV disease. However, resistance to both modalities remains a challenge. This is exemplified by our comprehensive analysis of a patient presenting with acral melanoma that developed resistance to both immune and targeted therapy.The patient developed metastatic disease in multiple sites and we obtained fresh tumour tissue and generated cell lines from a skin metastasis at baseline prior to nivolumab. Following an initial complete response, the patient developed new mediastinal lymph node and brain metastases, which were also resected. On further relapse, the patient commenced dabrafenib with a partial response. Despite ongoing extra-cranial control, the brain lesion progressed and was therefore resected.To investigate resistance to immune therapy, we performed comprehensive genomic analysis and gene expression profiling on the lesions from the three sites, which identified common mutations in all three lesions and a low overall mutational burden consistent with acral melanoma. Heterogeneity of the MHC class I and II restricted antigen profile of the pre-treatment subcutaneous metastasis versus lymph node and brain progressions could not account for the development of resistance to immunotherapy. Gene expression profiling revealed up-regulation of known mechanisms of immune tolerance in both the lymph node and brain metastasis compared to the pre-treatment subcutaneous metastasis.To investigate resistance to targeted therapy, we compared patient-derived cell lines from brain lesions taken pre (DabS) and on progression on dabrafenib (DabR), and showed ongoing sensitivity to dabrafenib despite the patient having progressed in the brain. When cells from the DabR cell line were cultured in cerebrospinal fluid (CSF) in the presence of dabrafenib, we observed a reduction in cell death. Thus, extrinsic factors present in CSF may have resulted in the progression of the brain lesion in this patient.Using a combination of platforms to study patient derived tissues, we show that immune editing through selection of cells with an immune resistant phenotype may have resulted in the resistance of this patient?s tumours to immune therapy whilst resistance to MAPK targeted therapy could have been mediated by extrinsic factors in the CSF.