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1.
Cell Rep ; 41(12): 111826, 2022 12 20.
Article in English | MEDLINE | ID: mdl-36543138

ABSTRACT

Cancer therapies trigger diverse cellular responses, ranging from apoptotic death to acquisition of persistent therapy-refractory states such as senescence. Tipping the balance toward apoptosis could improve treatment outcomes regardless of therapeutic agent or malignancy. We find that inhibition of the mitochondrial protein BCL-xL increases the propensity of cancer cells to die after treatment with a broad array of oncology drugs, including mitotic inhibitors and chemotherapy. Functional precision oncology and omics analyses suggest that BCL-xL inhibition redirects the outcome of p53 transcriptional response from senescence to apoptosis, which likely occurs via caspase-dependent down-modulation of p21 and downstream cytostatic proteins. Consequently, addition of a BCL-2/xL inhibitor strongly improves melanoma response to the senescence-inducing drug targeting mitotic kinase Aurora kinase A (AURKA) in mice and patient-derived organoids. This study shows a crosstalk between the mitochondrial apoptotic pathway and cell cycle regulation that can be targeted to augment therapeutic efficacy in cancers with wild-type p53.


Subject(s)
Antineoplastic Agents , Neoplasms , Animals , Mice , Tumor Suppressor Protein p53/metabolism , bcl-X Protein/metabolism , bcl-2-Associated X Protein/metabolism , Neoplasms/drug therapy , Precision Medicine , Apoptosis , Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins c-bcl-2/metabolism , Cell Line, Tumor
2.
Mol Cancer ; 20(1): 85, 2021 06 06.
Article in English | MEDLINE | ID: mdl-34092233

ABSTRACT

BACKGROUND: While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy. METHODS: Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data. RESULTS: RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB. CONCLUSIONS: Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone. TRIAL REGISTRATION: NCT01205815 (Sept 17, 2010).


Subject(s)
Antineoplastic Agents/pharmacology , CD40 Antigens/biosynthesis , Glycine/analogs & derivatives , Immune Checkpoint Inhibitors/pharmacology , Melanoma/pathology , Sulfones/pharmacology , ras Proteins/antagonists & inhibitors , Animals , Female , Glycine/pharmacology , Humans , Male , Melanoma/metabolism , Mice , Phosphatidylinositol 3-Kinases/drug effects , Protein Kinase Inhibitors/pharmacology , Signal Transduction/drug effects , Signal Transduction/physiology , Xenograft Model Antitumor Assays , raf Kinases/antagonists & inhibitors
3.
Clin Cancer Res ; 26(14): 3803-3818, 2020 07 15.
Article in English | MEDLINE | ID: mdl-32234759

ABSTRACT

PURPOSE: Over 60% of patients with melanoma respond to immune checkpoint inhibitor (ICI) therapy, but many subsequently progress on these therapies. Second-line targeted therapy is based on BRAF mutation status, but no available agents are available for NRAS, NF1, CDKN2A, PTEN, and TP53 mutations. Over 70% of melanoma tumors have activation of the MAPK pathway due to BRAF or NRAS mutations, while loss or mutation of CDKN2A occurs in approximately 40% of melanomas, resulting in unregulated MDM2-mediated ubiquitination and degradation of p53. Here, we investigated the therapeutic efficacy of over-riding MDM2-mediated degradation of p53 in melanoma with an MDM2 inhibitor that interrupts MDM2 ubiquitination of p53, treating tumor-bearing mice with the MDM2 inhibitor alone or combined with MAPK-targeted therapy. EXPERIMENTAL DESIGN: To characterize the ability of the MDM2 antagonist, KRT-232, to inhibit tumor growth, we established patient-derived xenografts (PDX) from 15 patients with melanoma. Mice were treated with KRT-232 or a combination with BRAF and/or MEK inhibitors. Tumor growth, gene mutation status, as well as protein and protein-phosphoprotein changes, were analyzed. RESULTS: One-hundred percent of the 15 PDX tumors exhibited significant growth inhibition either in response to KRT-232 alone or in combination with BRAF and/or MEK inhibitors. Only BRAFV600WT tumors responded to KRT-232 treatment alone while BRAFV600E/M PDXs exhibited a synergistic response to the combination of KRT-232 and BRAF/MEK inhibitors. CONCLUSIONS: KRT-232 is an effective therapy for the treatment of either BRAFWT or PAN WT (BRAFWT, NRASWT) TP53WT melanomas. In combination with BRAF and/or MEK inhibitors, KRT-232 may be an effective treatment strategy for BRAFV600-mutant tumors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Melanoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors , Skin Neoplasms/drug therapy , Adult , Aged , Animals , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cell Line, Tumor , Female , Humans , MAP Kinase Signaling System/drug effects , Male , Melanoma/genetics , Melanoma/pathology , Mice , Middle Aged , Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors , Mitogen-Activated Protein Kinase Kinases/metabolism , Mutation , Protein Kinase Inhibitors/therapeutic use , Proteolysis/drug effects , Proto-Oncogene Proteins B-raf/antagonists & inhibitors , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/metabolism , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Tumor Suppressor Protein p53/metabolism , Ubiquitination/drug effects , Xenograft Model Antitumor Assays
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