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2.
Nat Commun ; 10(1): 620, 2019 02 06.
Article in English | MEDLINE | ID: mdl-30728358

ABSTRACT

Elevated MYC expression sensitizes tumor cells to apoptosis but the therapeutic potential of this mechanism remains unclear. We find, in a model of MYC-driven breast cancer, that pharmacological activation of AMPK strongly synergizes with BCL-2/BCL-XL inhibitors to activate apoptosis. We demonstrate the translational potential of an AMPK and BCL-2/BCL-XL co-targeting strategy in ex vivo and in vivo models of MYC-high breast cancer. Metformin combined with navitoclax or venetoclax efficiently inhibited tumor growth, conferred survival benefits and induced tumor infiltration by immune cells. However, withdrawal of the drugs allowed tumor re-growth with presentation of PD-1+/CD8+ T cell infiltrates, suggesting immune escape. A two-step treatment regimen, beginning with neoadjuvant metformin+venetoclax to induce apoptosis and followed by adjuvant metformin+venetoclax+anti-PD-1 treatment to overcome immune escape, led to durable antitumor responses even after drug withdrawal. We demonstrate that pharmacological reactivation of MYC-dependent apoptosis is a powerful antitumor strategy involving both tumor cell depletion and immunosurveillance.


Subject(s)
Antibodies, Monoclonal/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Genes, myc/drug effects , Immunotherapy , Aniline Compounds/pharmacology , Animals , Antibodies, Monoclonal, Humanized , Apoptosis/immunology , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , CD8-Positive T-Lymphocytes , Cell Line, Tumor/drug effects , Cell Survival/drug effects , Clustered Regularly Interspaced Short Palindromic Repeats , Drug Combinations , Female , HEK293 Cells , Heterografts , Humans , Metformin/pharmacology , Mice , Mice, Transgenic , Proto-Oncogene Proteins c-bcl-2 , Sulfonamides/pharmacology , bcl-X Protein
3.
Clin Cancer Res ; 23(21): 6697-6707, 2017 Nov 01.
Article in English | MEDLINE | ID: mdl-28821556

ABSTRACT

Purpose: Dasatinib is a short-acting dual ABL/SRC family tyrosine kinase inhibitor (TKI), which is frequently used to treat chronic myeloid leukemia. Although very effective, patients taking dasatinib often display severe adverse effects, including pleural effusions and increased risk of bleeding primarily in the gastrointestinal tract. The actual causes of these side effects are currently undetermined. We hypothesize that endothelial cells (ECs) that line the inner walls of blood vessels and control the traffic to the underlying tissues might be involved.Experimental Design: The effects of TKIs on ECs were studied by various assays, such as real-time cell impedance measurements, live-cell microscopy, wound healing, Western blot, and an in vivo model.Results: Dasatinib uniquely causes a profound, dose-dependent disorganization of the EC monolayers. Dasatinib promoted the disassembly of cell-cell contacts, altered cell-matrix contacts, and further altered the wound healing. A key observation is that this effect is fully reversible after drug washout. In line with these in vitro observations, intraperitoneal administration of dasatinib to mice caused significant vascular leakage in the intestine. The underlying molecular mechanism of dasatinib-induced reorganization of the actin involves ROCK activation, which increases the amount of the phosphorylation of myosin light chain and consequently activates the non-muscle myosin II.Conclusions: Our data are consistent with a scenario in which dasatinib triggers a transient increase in vascular leakage that probably contributes to adverse effects such as bleeding diathesis and pleural effusions. Clin Cancer Res; 23(21); 6697-707. ©2017 AACR.


Subject(s)
Dasatinib/administration & dosage , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Molecular Motor Proteins/agonists , rho-Associated Kinases/genetics , Actins/metabolism , Animals , Cell Line, Tumor , Dasatinib/adverse effects , Endothelial Cells/drug effects , Endothelial Cells/pathology , Gene Expression Regulation, Neoplastic/drug effects , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mice , Myosin Heavy Chains , Wound Healing/drug effects , Xenograft Model Antitumor Assays , rho-Associated Kinases/metabolism
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