Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Blood ; 137(7): 939-944, 2021 02 18.
Article in English | MEDLINE | ID: mdl-32898857

ABSTRACT

Blinatumomab is currently approved for use as a single agent in relapsed and refractory acute lymphoblastic leukemia (ALL). Cytotoxicity is mediated via signaling through the T-cell receptor (TCR). There is now much interest in combining blinatumomab with targeted therapies, particularly in Philadelphia chromosome-positive ALL (Ph+ ALL). However, some second- and third-generation ABL inhibitors also potently inhibit Src family kinases that are important in TCR signaling. We combined ABL inhibitors and dual Src/ABL inhibitors with blinatumomab in vitro from both healthy donor samples and primary samples from patients with Ph+ ALL. Blinatumomab alone led to both T-cell proliferation and elimination of target CD19+ cells and enhanced production of interferon-γ (IFN-γ). The addition of the ABL inhibitors imatinib or nilotinib to blinatumomab did not inhibit T-cell proliferation or IFN-γ production. However, the addition of dasatinib or ponatinib inhibited T-cell proliferation and IFN-γ production. Importantly, there was no loss of CD19+ cells treated with blinatumomab plus dasatinib or ponatinib in healthy samples or samples with a resistant ABL T315I mutation by dasatinib in combination with blinatumomab. These in vitro findings bring pause to the excitement of combination therapies, highlighting the importance of maintaining T-cell function with targeted therapies.


Subject(s)
Antibodies, Bispecific/pharmacology , Antineoplastic Agents/pharmacology , Fusion Proteins, bcr-abl/antagonists & inhibitors , Lymphocyte Activation/drug effects , Neoplasm Proteins/antagonists & inhibitors , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , T-Lymphocytes/immunology , src-Family Kinases/antagonists & inhibitors , B-Lymphocytes , Dasatinib/pharmacology , Humans , Imatinib Mesylate/pharmacology , Imidazoles/pharmacology , Interferon-gamma Release Tests , Jurkat Cells , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism , Mutation, Missense , Neoplasm Proteins/physiology , Phosphorylation/drug effects , Point Mutation , Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/immunology , Protein Processing, Post-Translational/drug effects , Proto-Oncogene Proteins c-abl/genetics , Pyridazines/pharmacology , Pyrimidines/pharmacology , Receptors, Antigen, T-Cell/metabolism , T-Lymphocytes/enzymology , T-Lymphocytes/metabolism , Tumor Cells, Cultured , src-Family Kinases/physiology
2.
Cancer Cell ; 31(6): 790-803.e8, 2017 06 12.
Article in English | MEDLINE | ID: mdl-28609657

ABSTRACT

The androgen receptor (AR) is critical for the progression of prostate cancer to a castration-resistant (CRPC) state. AR antagonists are ineffective due to their inability to repress the expression of AR or its splice variant, AR-V7. Here, we report that the tyrosine kinase ACK1 (TNK2) phosphorylates histone H4 at tyrosine 88 upstream of the AR transcription start site. The WDR5/MLL2 complex reads the H4-Y88-phosphorylation marks and deposits the transcriptionally activating H3K4-trimethyl marks promoting AR transcription. Reversal of the pY88-H4 epigenetic marks by the ACK1 inhibitor (R)-9bMS-sensitized naive and enzalutamide-resistant prostate cancer cells and reduced AR and AR-V7 levels to mitigate CRPC tumor growth. Thus, a feedforward ACK1/pY88-H4/WDR5/MLL2/AR epigenetic circuit drives CRPC and is necessary for maintenance of the malignant state.


Subject(s)
Gene Expression Regulation, Neoplastic , Histones/metabolism , Prostatic Neoplasms, Castration-Resistant/genetics , Protein-Tyrosine Kinases/physiology , Receptors, Androgen/genetics , Benzamides , Cell Proliferation/drug effects , Drug Resistance, Neoplasm , Epigenesis, Genetic , Humans , Male , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/therapeutic use , Phosphorylation , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , RNA, Messenger/metabolism , Receptors, Androgen/metabolism , Tumor Cells, Cultured
3.
Oncotarget ; 8(63): 106352-106368, 2017 Dec 05.
Article in English | MEDLINE | ID: mdl-29290954

ABSTRACT

Epigenetic signaling networks dynamically regulate gene expression to maintain cellular homeostasis. Previously, we uncovered that WEE1 phosphorylates histone H2B at tyrosine 37 (pY37-H2B) to negatively regulate global histone transcriptional output. Although pY37-H2B is readily detected in cancer cells, its functional role in pathogenesis is not known. Herein, we show that WEE1 deposits the pY37-H2B marks within the tumor suppressor gene, isocitrate dehydrogenase 2 (IDH2), to repress transcription in multiple cancer cells, including glioblastoma multiforme (GBMs), melanoma and prostate cancer. Consistently, GBMs and primary melanoma tumors that display elevated WEE1 mRNA expression exhibit significant down regulation of the IDH2 gene transcription. IDH2 catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG), an essential cofactor for the TET family of 5-methylcytosine (5mC) hydroxylases that convert 5-mC to 5-hydroxymethylcytosine (5-hmC). Significantly, the WEE1 inhibitor AZD1775 not only abrogated the suppressive H2B Y37-phosphorylation and upregulated IDH2 mRNA levels but also effectively reversed the 'loss of 5-hmC' phenotype in melanomas, GBMs and prostate cancer cells, as well as melanoma xenograft tumors. These data indicate that the epigenetic repression of IDH2 by WEE1/pY37-H2B circuit may be a hitherto unknown mechanism of global 5-hmC loss observed in human malignancies.

4.
Oncotarget ; 8(2): 2971-2983, 2017 01 10.
Article in English | MEDLINE | ID: mdl-27902967

ABSTRACT

Breast cancer is the most prevalent cancer in women worldwide. About 15-20% of all breast cancers do not express estrogen receptor, progesterone receptor or HER2 receptor and hence are collectively classified as triple negative breast cancer (TNBC). These tumors are often relatively aggressive when compared to other types of breast cancer, and this issue is compounded by the lack of effective targeted therapy. In our previous phosphoproteomic profiling effort, we identified the non-receptor tyrosine kinase TNK2 as activated in a majority of aggressive TNBC cell lines. In the current study, we show that high expression of TNK2 in breast cancer cell lines correlates with high proliferation, invasion and colony forming ability. We demonstrate that knockdown of TNK2 expression can substantially suppress the invasiveness and proliferation advantage of TNBC cells in vitro and tumor formation in xenograft mouse models. Moreover, inhibition of TNK2 with small molecule inhibitor (R)-9bMS significantly compromised TNBC proliferation.Finally, we find that high levels of TNK2 expression in high-grade basal-like breast cancers correlates significantly with poorer patient outcome. Taken together, our study suggests that TNK2 is a novel potential therapeutic target for the treatment of TNBC.


Subject(s)
Antineoplastic Agents/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/metabolism , Triple Negative Breast Neoplasms/metabolism , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Disease Progression , Female , Gene Expression , Gene Knockdown Techniques , Humans , Mice , Phosphorylation , Prognosis , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/genetics , Survival Rate , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays
SELECTION OF CITATIONS
SEARCH DETAIL
...