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1.
Cell Rep ; 39(1): 110634, 2022 04 05.
Article in English | MEDLINE | ID: mdl-35385748

ABSTRACT

Although combination BRAF/MEK inhibition has produced significant survival benefits for BRAF p.V600 mutant melanomas, targeted therapies approved for BRAF non-p.V600 mutant melanomas remain limited. Through the analysis of 772 cutaneous melanoma exomes, we reveal that BRAF non-p.V600 mutations co-occurs more frequently with NF1 loss, but not with oncogenic NRAS mutations, than expected by chance. We present cell signaling data, which demonstrate that BRAF non-p.V600 mutants can signal as monomers and dimers within an NF1 loss context. Concordantly, BRAF inhibitors that inhibit both monomeric and dimeric BRAF synergize with MEK inhibition to significantly reduce cell viability in vitro and tumor growth in vivo in BRAF non-p.V600 mutant melanomas with co-occurring NF1 loss-of-function mutations. Our data suggest that patients harboring BRAF non-p.V600 mutant melanomas may benefit from current FDA-approved BRAF/MEK inhibitor combination therapy currently reserved for BRAF p.V600 mutant patients.


Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/drug therapy , Melanoma/genetics , Mitogen-Activated Protein Kinase Kinases/genetics , Mutation/genetics , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/genetics , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics
2.
Sci Immunol ; 7(70): eabi5072, 2022 04.
Article in English | MEDLINE | ID: mdl-35363543

ABSTRACT

Melanoma is an immunogenic cancer with a high response rate to immune checkpoint inhibitors (ICIs). It harbors a high mutation burden compared with other cancers and, as a result, has abundant tumor-infiltrating lymphocytes (TILs) within its microenvironment. However, understanding the complex interplay between the stroma, tumor cells, and distinct TIL subsets remains a substantial challenge in immune oncology. To properly study this interplay, quantifying spatial relationships of multiple cell types within the tumor microenvironment is crucial. To address this, we used cytometry time-of-flight (CyTOF) imaging mass cytometry (IMC) to simultaneously quantify the expression of 35 protein markers, characterizing the microenvironment of 5 benign nevi and 67 melanomas. We profiled more than 220,000 individual cells to identify melanoma, lymphocyte subsets, macrophage/monocyte, and stromal cell populations, allowing for in-depth spatial quantification of the melanoma microenvironment. We found that within pretreatment melanomas, the abundance of proliferating antigen-experienced cytotoxic T cells (CD8+CD45RO+Ki67+) and the proximity of antigen-experienced cytotoxic T cells to melanoma cells were associated with positive response to ICIs. Our study highlights the potential of multiplexed single-cell technology to quantify spatial cell-cell interactions within the tumor microenvironment to understand immune therapy responses.


Subject(s)
Melanoma , Humans , Image Cytometry , Lymphocytes, Tumor-Infiltrating , T-Lymphocytes, Cytotoxic , Tumor Microenvironment
3.
Mol Cancer Ther ; 20(1): 64-75, 2021 01.
Article in English | MEDLINE | ID: mdl-33087508

ABSTRACT

Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare but often lethal cancer that is diagnosed at a median age of 24 years. Optimal management of patients is not well defined, and current treatment remains challenging, necessitating the discovery of novel therapeutic approaches. The identification of SMARCA4-inactivating mutations invariably characterizing this type of cancer provided insights facilitating diagnostic and therapeutic measures against this disease. We show here that the BET inhibitor OTX015 acts in synergy with the MEK inhibitor cobimetinib to repress the proliferation of SCCOHT in vivo Notably, this synergy is also observed in some SMARCA4-expressing ovarian adenocarcinoma models intrinsically resistant to BETi. Mass spectrometry, coupled with knockdown of newly found targets such as thymidylate synthase, revealed that the repression of a panel of proteins involved in nucleotide synthesis underlies this synergy both in vitro and in vivo, resulting in reduced pools of nucleotide metabolites and subsequent cell-cycle arrest. Overall, our data indicate that dual treatment with BETi and MEKi represents a rational combination therapy against SCCOHT and potentially additional ovarian cancer subtypes.


Subject(s)
Epigenesis, Genetic , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Nucleotides/metabolism , Protein Kinase Inhibitors/pharmacology , Animals , Azetidines/pharmacology , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Down-Regulation/drug effects , Drug Synergism , Epigenesis, Genetic/drug effects , Female , Gene Knockdown Techniques , HEK293 Cells , Humans , Mice, Inbred NOD , Mice, SCID , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Mitogen-Activated Protein Kinases/metabolism , Neoplasm Proteins/metabolism , Ovarian Neoplasms/drug therapy , Piperidines/pharmacology , Protein Kinase Inhibitors/therapeutic use , S Phase/drug effects , Xenograft Model Antitumor Assays
4.
Clin Cancer Res ; 24(24): 6483-6494, 2018 12 15.
Article in English | MEDLINE | ID: mdl-29903896

ABSTRACT

PURPOSE: Dual MAPK pathway inhibition (dMAPKi) with BRAF and MEK inhibitors improves survival in BRAF V600E/K mutant melanoma, but the efficacy of dMAPKi in non-V600 BRAF mutant tumors is poorly understood. We sought to characterize the responsiveness of class II (enhanced kinase activity, dimerization dependent) BRAF mutant melanoma to dMAPKi. EXPERIMENTAL DESIGN: Tumors from patients with BRAF wild-type (WT), V600E (class I), and L597S (class II) metastatic melanoma were used to generate patient-derived xenografts (PDX). We assembled a panel of melanoma cell lines with class IIa (activation segment) or IIb (p-loop) mutations and compared these with WT or V600E/K BRAF mutant cells. Cell lines and PDXs were treated with BRAFi (vemurafenib, dabrafenib, encorafenib, and LY3009120), MEKi (cobimetinib, trametinib, and binimetinib), or the combination. We identified 2 patients with BRAF L597S metastatic melanoma who were treated with dMAPKi. RESULTS: BRAFi impaired MAPK signaling and cell growth in class I and II BRAF mutant cells. dMAPKi was more effective than either single MAPKi at inhibiting cell growth in all class II BRAF mutant cells tested. dMAPKi caused tumor regression in two melanoma PDXs with class II BRAF mutations and prolonged survival of mice with class II BRAF mutant melanoma brain metastases. Two patients with BRAF L597S mutant melanoma clinically responded to dMAPKi. CONCLUSIONS: Class II BRAF mutant melanoma is growth inhibited by dMAPKi. Responses to dMAPKi have been observed in 2 patients with class II BRAF mutant melanoma. These data provide rationale for clinical investigation of dMAPKi in patients with class II BRAF mutant metastatic melanoma.See related commentary by Johnson and Dahlman, p. 6107.


Subject(s)
Antineoplastic Agents/pharmacology , Melanoma/genetics , Melanoma/metabolism , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Mutation , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/genetics , Animals , Antineoplastic Agents/therapeutic use , Biopsy , Brain Neoplasms/diagnostic imaging , Brain Neoplasms/drug therapy , Brain Neoplasms/secondary , Cell Line, Tumor , Computational Biology/methods , Disease Models, Animal , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , Melanoma/diagnosis , Melanoma/drug therapy , Mice , Protein Kinase Inhibitors/therapeutic use , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Signal Transduction/drug effects , Tomography, X-Ray Computed , Xenograft Model Antitumor Assays
5.
Oncogene ; 37(24): 3183-3199, 2018 06.
Article in English | MEDLINE | ID: mdl-29540830

ABSTRACT

The RAS-RAF-MEK-ERK signaling cascade is among the most frequently mutated pathways in human cancer. Approximately 50% of melanoma patients possess a druggable hotspot V600E/K mutation in the BRAF protein kinase. FDA-approved combination therapies of BRAF and MEK inhibitors are available that provide survival benefits to patients with a BRAF V600 mutation. Non-V600 BRAF mutants are found in many cancers, and are more prevalent than V600 mutations in certain tumor types. For example, between 50-80% of BRAF mutations in non-small cell lung cancer and 22-30% in colorectal cancer encode for non-V600 mutants. As next generation sequencing becomes increasingly used in clinical practice, oncologists are frequently identifying non-V600 BRAF mutations in their patient's tumors, but are uncertain of viable therapeutic options that could be employed for optimal treatment. From recent studies, a new classification system is emerging for BRAF mutations based on biochemical and signaling mechanisms associated with these mutants. Class I BRAF mutations affect amino acid V600 and signal as RAS-independent active monomers, class II mutations function as RAS-independent activated dimers, and class III mutations are kinase impaired but increase signaling through the MAPK pathway due to enhanced RAS binding and subsequent CRAF activation. These distinct classes of BRAF mutations predict response to targeted therapies and have important implications for future drug development. Herein, we discuss pre-clinical and clinical findings that may lead to improved treatments for all classes of BRAF mutant cancers.


Subject(s)
Antineoplastic Agents/pharmacology , Mutation , Neoplasms/genetics , Proto-Oncogene Proteins B-raf/genetics , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Humans , Lung Neoplasms/genetics , Lung Neoplasms/mortality , MAP Kinase Signaling System/drug effects , Melanoma/genetics , Melanoma/mortality , Molecular Targeted Therapy/methods , Neoplasms/drug therapy , Protein Domains , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/chemistry
6.
Br J Cancer ; 115(2): 145-55, 2016 Jul 12.
Article in English | MEDLINE | ID: mdl-27336610

ABSTRACT

Large-scale genomic analyses of cutaneous melanoma have revealed insights into the aetiology and heterogeneity of this disease, as well as opportunities to further personalise treatment for patients with targeted and immune therapies. Herein, we review the proposed genomic classification of cutaneous melanoma from large-scale next-generation sequencing studies, including the largest integrative analysis of melanoma from The Cancer Genome Atlas (TCGA) Network. We examine studies that have identified molecular features of melanomas linked to immune checkpoint inhibitor response. In addition, we draw attention to low-frequency actionable mutations and highlight frequent non-coding mutations in melanoma where little is known about their biological function that may provide novel avenues for the development of treatment strategies for melanoma patients.


Subject(s)
Melanoma/genetics , Melanoma/therapy , Skin Neoplasms/genetics , Skin Neoplasms/therapy , Atlases as Topic , Humans , Immunotherapy , Mutation
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