ABSTRACT
Targeted treatment of advanced melanoma could benefit from the precise molecular characterization of melanoma samples. Using a melanoma-specific selection of 217 genes, we performed targeted deep sequencing of a series of biopsies, from advanced melanoma cases, with a Breslow index of ≥ 4 mm, and/or with a loco-regional infiltration in lymph nodes or presenting distant metastasis, as well of a collection of human cell lines. This approach detected 3-4 mutations per case, constituting unique mutational signatures associated with specific inhibitor sensitivity. Functionally, case-specific combinations of inhibitors that simultaneously targeted MAPK-dependent and MAPK-independent mechanisms were most effective at inhibiting melanoma growth, against each specific mutational background. These observations were challenged by characterizing a freshly resected biopsy from a metastatic lesion located in the skin and soft tissue and by testing its associated therapy ex vivo and in vivo using melanocytes and patient-derived xenografted mice, respectively. The results show that upon mutational characterization of advanced melanoma patients, specific mutational profiles can be used for selecting drugs that simultaneously target several deregulated genes/pathways involved in tumor generation or progression.
Subject(s)
Antineoplastic Agents/therapeutic use , Biomarkers, Tumor/genetics , DNA Mutational Analysis/methods , Gene Expression Profiling/methods , Melanoma/drug therapy , Melanoma/genetics , Mutation , Precision Medicine , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Animals , Biopsy , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Genetic Predisposition to Disease , Humans , Lymphatic Metastasis , Melanocytes/drug effects , Melanocytes/metabolism , Melanocytes/pathology , Melanoma/secondary , Mice, Inbred BALB C , Mice, Inbred NOD , Mice, Nude , Molecular Targeted Therapy , Patient Selection , Phenotype , Predictive Value of Tests , Protein Kinase Inhibitors/therapeutic use , Signal Transduction/drug effects , Skin Neoplasms/pathology , Time Factors , Xenograft Model Antitumor AssaysSubject(s)
Janus Kinases/genetics , Janus Kinases/metabolism , Lymphoma, T-Cell, Cutaneous , STAT Transcription Factors/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Adult , Aged , Aged, 80 and over , Female , Humans , Lymphoma, T-Cell, Cutaneous/drug therapy , Lymphoma, T-Cell, Cutaneous/genetics , Lymphoma, T-Cell, Cutaneous/metabolism , Male , Middle Aged , STAT Transcription Factors/geneticsABSTRACT
Currently, there is no efficient therapy for patients with peripheral T cell lymphoma (PTCL). The Proviral Integration site of Moloney murine leukemia virus (PIM) kinases are important mediators of cell survival. We aimed to determine the therapeutic value of PIM kinases because they are overexpressed in PTCL patients, T cell lines and primary tumoral T cells. PIM kinases were inhibited genetically (using small interfering and short hairpin RNAs) and pharmacologically (mainly with the pan-PIM inhibitor (PIMi) ETP-39010) in a panel of 8 PTCL cell lines. Effects on cell viability, apoptosis, cell cycle, key proteins and gene expression were evaluated. Individual inhibition of each of the PIM genes did not affect PTCL cell survival, partially because of a compensatory mechanism among the three PIM genes. In contrast, pharmacological inhibition of all PIM kinases strongly induced apoptosis in all PTCL cell lines, without cell cycle arrest, in part through the induction of DNA damage. Therefore, pan-PIMi synergized with Cisplatin. Importantly, pharmacological inhibition of PIM reduced primary tumoral T cell viability without affecting normal T cells ex vivo. Since anaplastic large cell lymphoma (ALK+ ALCL) cell lines were the most sensitive to the pan-PIMi, we tested the simultaneous inhibition of ALK and PIM kinases and found a strong synergistic effect in ALK+ ALCL cell lines. Our findings suggest that PIM kinase inhibition could be of therapeutic value in a subset of PTCL, especially when combined with ALK inhibitors, and might be clinically beneficial in ALK+ ALCL.
