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MDM2 antagonists overcome intrinsic resistance to CDK4/6 inhibition by inducing p21.
Vilgelm AE, Saleh N, Shattuck-Brandt R, Riemenschneider K, Slesur L, Chen SC, Johnson CA, Yang J, Blevins A, Yan C, Johnson DB, Al-Rohil RN, Halilovic E, Kauffmann RM, Kelley M, Ayers GD, Richmond A
(2019) Sci Transl Med 11:
MeSH Terms: Analysis of Variance, Animals, Blotting, Western, Cell Cycle, Cell Survival, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p21, DNA Replication, Dimethyl Sulfoxide, Humans, Immunoprecipitation, MCF-7 Cells, Melanoma, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Nude, Proteomics, Proto-Oncogene Proteins c-mdm2, Radioimmunoprecipitation Assay
Show Abstract · Added September 27, 2019
Intrinsic resistance of unknown mechanism impedes the clinical utility of inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) in malignancies other than breast cancer. Here, we used melanoma patient-derived xenografts (PDXs) to study the mechanisms for CDK4/6i resistance in preclinical settings. We observed that melanoma PDXs resistant to CDK4/6i frequently displayed activation of the phosphatidylinositol 3-kinase (PI3K)-AKT pathway, and inhibition of this pathway improved CDK4/6i response in a p21-dependent manner. We showed that a target of p21, CDK2, was necessary for proliferation in CDK4/6i-treated cells. Upon treatment with CDK4/6i, melanoma cells up-regulated cyclin D1, which sequestered p21 and another CDK inhibitor, p27, leaving a shortage of p21 and p27 available to bind and inhibit CDK2. Therefore, we tested whether induction of p21 in resistant melanoma cells would render them responsive to CDK4/6i. Because p21 is transcriptionally driven by p53, we coadministered CDK4/6i with a murine double minute (MDM2) antagonist to stabilize p53, allowing p21 accumulation. This resulted in improved antitumor activity in PDXs and in murine melanoma. Furthermore, coadministration of CDK4/6 and MDM2 antagonists with standard of care therapy caused tumor regression. Notably, the molecular features associated with response to CDK4/6 and MDM2 inhibitors in PDXs were recapitulated by an ex vivo organotypic slice culture assay, which could potentially be adopted in the clinic for patient stratification. Our findings provide a rationale for cotargeting CDK4/6 and MDM2 in melanoma.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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21 MeSH Terms
Identification of Targetable Recurrent MAP3K8 Rearrangements in Melanomas Lacking Known Driver Mutations.
Lehmann BD, Shaver TM, Johnson DB, Li Z, Gonzalez-Ericsson PI, Sánchez V, Shyr Y, Sanders ME, Pietenpol JA
(2019) Mol Cancer Res 17: 1842-1853
MeSH Terms: Algorithms, Cell Line, Tumor, Databases, Genetic, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Kinase Kinases, Male, Melanoma, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Sequence Analysis, RNA, Sequence Deletion, Survival Analysis, Translocation, Genetic, Up-Regulation
Show Abstract · Added March 30, 2020
Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma, we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in more than 15% of tumors without known driver mutations (, and ). Using an independent tumor set, we validated a similar rearrangement frequency by FISH. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells result in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma, and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements. IMPLICATIONS: This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.
©2019 American Association for Cancer Research.
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17 MeSH Terms
Quantifying Drug Combination Synergy along Potency and Efficacy Axes.
Meyer CT, Wooten DJ, Paudel BB, Bauer J, Hardeman KN, Westover D, Lovly CM, Harris LA, Tyson DR, Quaranta V
(2019) Cell Syst 8: 97-108.e16
MeSH Terms: Drug Combinations, Drug Synergism, Humans, Melanoma
Show Abstract · Added March 23, 2019
Two goals motivate treating diseases with drug combinations: reduce off-target toxicity by minimizing doses (synergistic potency) and improve outcomes by escalating effect (synergistic efficacy). Established drug synergy frameworks obscure such distinction, failing to harness the potential of modern chemical libraries. We therefore developed multi-dimensional synergy of combinations (MuSyC), a formalism based on a generalized, multi-dimensional Hill equation, which decouples synergistic potency and efficacy. In mutant-EGFR-driven lung cancer, MuSyC reveals that combining a mutant-EGFR inhibitor with inhibitors of other kinases may result only in synergistic potency, whereas synergistic efficacy can be achieved by co-targeting mutant-EGFR and epigenetic regulation or microtubule polymerization. In mutant-BRAF melanoma, MuSyC determines whether a molecular correlate of BRAFi insensitivity alters a BRAF inhibitor's potency, efficacy, or both. These findings showcase MuSyC's potential to transform the enterprise of drug-combination screens by precisely guiding translation of combinations toward dose reduction, improved efficacy, or both.
Copyright © 2019 Elsevier Inc. All rights reserved.
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4 MeSH Terms
Response to Anti-PD-1 in Uveal Melanoma Without High-Volume Liver Metastasis.
Johnson DB, Bao R, Ancell KK, Daniels AB, Wallace D, Sosman JA, Luke JJ
(2019) J Natl Compr Canc Netw 17: 114-117
MeSH Terms: Antineoplastic Agents, Immunological, Computational Biology, Gene Expression Profiling, Humans, Liver Neoplasms, Melanoma, Molecular Targeted Therapy, Neoplasm Staging, Prognosis, Programmed Cell Death 1 Receptor, Treatment Outcome, Uveal Neoplasms
Show Abstract · Added March 30, 2020
Uveal melanoma (UM) is an uncommon melanoma subtype with poor prognosis. Agents that have transformed the management of cutaneous melanoma have made minimal inroads in UM. We conducted a single-arm phase II study of pembrolizumab in patients with metastatic UM and performed bioinformatics analyses of publicly available datasets to characterize the activity of anti-PD-1 in this setting and to understand the mutational and immunologic profile of this disease. A total of 5 patients received pembrolizumab in this study. Median overall survival was not reached, and median progression-free survival was 11.0 months. One patient experienced a complete response after one dose and 2 others experienced prolonged stable disease (20% response rate, 60% clinical benefit rate); 2 additional patients had rapidly progressing disease. Notably, the patients who benefited had either no liver metastases or small-volume disease, whereas patients with rapidly progressing disease had bulky liver involvement. We performed a bioinformatics analysis of The Cancer Genome Atlas for UM and confirmed a low mutation burden and low rates of T-cell inflammation. Note that the lack of T-cell inflammation strongly correlated with pathway overexpression. Anti-PD-1-based therapy may cause clinical benefit in metastatic UM, seemingly more often in patients without bulky liver metastases. Lack of mutation burden and T-cell infiltration and overexpression may be factors limiting therapeutic responses. NCT02359851.
Copyright © 2019 by the National Comprehensive Cancer Network.
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12 MeSH Terms
Impaired enolase 1 glycolytic activity restrains effector functions of tumor-infiltrating CD8 T cells.
Gemta LF, Siska PJ, Nelson ME, Gao X, Liu X, Locasale JW, Yagita H, Slingluff CL, Hoehn KL, Rathmell JC, Bullock TNJ
(2019) Sci Immunol 4:
MeSH Terms: Animals, Antineoplastic Agents, Immunological, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Glucose, Glucose Transporter Type 1, Glycolysis, Hepatitis A Virus Cellular Receptor 2, Humans, Immunoglobulin G, Immunotherapy, Adoptive, Lymphocytes, Tumor-Infiltrating, Melanoma, Mice, Inbred C57BL, Phosphopyruvate Hydratase, Programmed Cell Death 1 Receptor
Show Abstract · Added March 30, 2020
In the context of solid tumors, there is a positive correlation between the accumulation of cytotoxic CD8 tumor-infiltrating lymphocytes (TILs) and favorable clinical outcomes. However, CD8 TILs often exhibit a state of functional exhaustion, limiting their activity, and the underlying molecular basis of this dysfunction is not fully understood. Here, we show that TILs found in human and murine CD8 melanomas are metabolically compromised with deficits in both glycolytic and oxidative metabolism. Although several studies have shown that tumors can outcompete T cells for glucose, thus limiting T cell metabolic activity, we report that a down-regulation in the activity of ENOLASE 1, a critical enzyme in the glycolytic pathway, represses glycolytic activity in CD8 TILs. Provision of pyruvate, a downstream product of ENOLASE 1, bypasses this inactivity and promotes both glycolysis and oxidative phosphorylation, resulting in improved effector function of CD8 TILs. We found high expression of both enolase 1 mRNA and protein in CD8 TILs, indicating that the enzymatic activity of ENOLASE 1 is regulated posttranslationally. These studies provide a critical insight into the biochemical basis of CD8 TIL dysfunction.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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1 Members
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16 MeSH Terms
Loss of CXCR4 in Myeloid Cells Enhances Antitumor Immunity and Reduces Melanoma Growth through NK Cell and FASL Mechanisms.
Yang J, Kumar A, Vilgelm AE, Chen SC, Ayers GD, Novitskiy SV, Joyce S, Richmond A
(2018) Cancer Immunol Res 6: 1186-1198
MeSH Terms: Animals, Bone Marrow Transplantation, Cell Line, Tumor, Cytotoxicity, Immunologic, Fas Ligand Protein, Interleukin-18, Killer Cells, Natural, Macrophages, Melanoma, Experimental, Mice, Inbred C57BL, Mice, Transgenic, Neutrophils, Receptors, CXCR4
Show Abstract · Added December 20, 2018
The chemokine receptor, CXCR4, is involved in cancer growth, invasion, and metastasis. Several promising CXCR4 antagonists have been shown to halt tumor metastasis in preclinical studies, and clinical trials evaluating the effectiveness of these agents in patients with cancer are ongoing. However, the impact of targeting CXCR4 specifically on immune cells is not clear. Here, we demonstrate that genetic deletion of CXCR4 in myeloid cells (CXCR4) enhances the antitumor immune response, resulting in significantly reduced melanoma tumor growth. Moreover, CXCR4 mice exhibited slowed tumor progression compared with CXCR4 mice in an inducible melanocyte mouse model. The percentage of Fas ligand (FasL)-expressing myeloid cells was reduced in CXCR4 mice as compared with myeloid cells from CXCR4 mice. In contrast, there was an increased percentage of natural killer (NK) cells expressing FasL in tumors growing in CXCR4 mice. NK cells from CXCR4 mice also exhibited increased tumor cell killing capacity , based on clearance of NK-sensitive Yac-1 cells. NK cell-mediated killing of Yac-1 cells occurred in a FasL-dependent manner, which was partially dependent upon the presence of CXCR4 neutrophils. Furthermore, enhanced NK cell activity in CXCR4 mice was also associated with increased production of IL18 by specific leukocyte subpopulations. These data suggest that CXCR4-mediated signals from myeloid cells suppress NK cell-mediated tumor surveillance and thereby enhance tumor growth. Systemic delivery of a peptide antagonist of CXCR4 to tumor-bearing CXCR4 mice resulted in enhanced NK-cell activation and reduced tumor growth, supporting potential clinical implications for CXCR4 antagonism in some cancers. .
©2018 American Association for Cancer Research.
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2 Members
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13 MeSH Terms
Continued Poor Survival in Metastatic Uveal Melanoma: Implications for Molecular Prognostication, Surveillance Imaging, Adjuvant Therapy, and Clinical Trials.
Johnson DB, Daniels AB
(2018) JAMA Ophthalmol 136: 986-988
MeSH Terms: Combined Modality Therapy, Humans, Melanoma, Survival Rate, Uveal Neoplasms
Added March 30, 2020
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MeSH Terms
BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors.
Doxie DB, Greenplate AR, Gandelman JS, Diggins KE, Roe CE, Dahlman KB, Sosman JA, Kelley MC, Irish JM
(2018) Pigment Cell Melanoma Res 31: 708-719
MeSH Terms: Antibodies, Neoplasm, Cell Line, Tumor, Humans, Imidazoles, Melanoma, Mitogen-Activated Protein Kinase Kinases, Nestin, Oximes, Phenotype, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones
Show Abstract · Added May 21, 2018
Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAF melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy. Approximately 50,000 cells per tumor were characterized by mass cytometry and computational tools t-SNE/viSNE, FlowSOM, and MEM. The resulting single-cell view of melanoma treatment response revealed initially heterogeneous melanoma tumors were consistently cleared of Nestin-expressing melanoma cells. Melanoma cell subsets that persisted to week 4 were heterogeneous but expressed SOX2 or SOX10 proteins and specifically lacked surface expression of MHC I proteins by MEM analysis. Traditional histology imaging of tissue microarrays from the same tumors confirmed mass cytometry results, including persistence of NES- SOX10+ S100β+ melanoma cells. This quantitative single-cell view of melanoma treatment response revealed protein features of malignant cells that are not eliminated by targeted therapy.
© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
2 Communities
1 Members
0 Resources
13 MeSH Terms
A Nonquiescent "Idling" Population State in Drug-Treated, BRAF-Mutated Melanoma.
Paudel BB, Harris LA, Hardeman KN, Abugable AA, Hayford CE, Tyson DR, Quaranta V
(2018) Biophys J 114: 1499-1511
MeSH Terms: Cell Line, Tumor, Drug Resistance, Neoplasm, Epigenesis, Genetic, Humans, Melanoma, Molecular Targeted Therapy, Mutation, Proto-Oncogene Proteins B-raf
Show Abstract · Added April 15, 2018
Targeted therapy is an effective standard of care in BRAF-mutated malignant melanoma. However, the duration of tumor remission varies unpredictably among patients, and relapse is almost inevitable. Here, we examine the responses of several BRAF-mutated melanoma cell lines (including isogenic subclones) to BRAF inhibitors. We observe complex response dynamics across cell lines, with short-term responses (<100 h) varying from cell line to cell line. In the long term, however, we observe equilibration of all drug-treated populations into a nonquiescent state characterized by a balanced rate of death and division, which we term the "idling" state, and to our knowledge, this state has not been previously reported. Using mathematical modeling, we propose that the observed population-level dynamics are the result of cells transitioning between basins of attraction within a drug-modified phenotypic landscape. Each basin is associated with a drug-induced proliferation rate, a recently introduced metric of an antiproliferative drug effect. The idling population state represents a new dynamic equilibrium in which cells are distributed across the landscape such that the population achieves zero net growth. By fitting our model to experimental drug-response data, we infer the phenotypic landscapes of all considered melanoma cell lines and provide a unifying view of how BRAF-mutated melanomas respond to BRAF inhibition. We hypothesize that the residual disease observed in patients after targeted therapy is composed of a significant number of idling cells. Thus, defining molecular determinants of the phenotypic landscape that idling populations occupy may lead to "targeted landscaping" therapies based on rational modification of the landscape to favor basins with greater drug susceptibility.
Copyright © 2018 Biophysical Society. Published by Elsevier Inc. All rights reserved.
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8 MeSH Terms
BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy.
Johnson DB, Childress MA, Chalmers ZR, Frampton GM, Ali SM, Rubinstein SM, Fabrizio D, Ross JS, Balasubramanian S, Miller VA, Stephens PJ, Sosman JA, Lovly CM
(2018) Pigment Cell Melanoma Res 31: 432-436
MeSH Terms: Adult, Amino Acid Substitution, Base Sequence, Drug Resistance, Neoplasm, Female, Humans, Imidazoles, MAP Kinase Signaling System, Melanoma, Mutation, Missense, Oximes, Protein Kinase Inhibitors, Proto-Oncogene Proteins B-raf, Pyridones, Pyrimidinones, Sequence Deletion
Show Abstract · Added September 10, 2020
BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAF -mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib. In addition to a preserved BRAF mutation, an internal deletion (rearrangement) of BRAF was observed in the progression sample. This deletion involved exons 2-8, which includes the Ras-binding domain, and is analogous to previously documented BRAF fusions and splice variants known to reactivate RAS-RAF-MEK-ERK signaling. In a large cohort of melanomas, 10 additional internal deletions were identified (0.4% of all melanomas; nine of which had concurrent BRAF mutations), as well as sporadically in other tumor types. Thus, we describe a novel mechanism of resistance to BRAF and MEK inhibition.
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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MeSH Terms