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Acute myeloid leukemia (AML) is caused by abnormal production of white blood cells, red blood cells or platelets. The leukemia cells communicate with their microenvironment through nano-vesicle exosomes that are 30-100 nm in diameter. These nano-vesicles are released from body fluids upon fusion of an endocytic compartment with the cell membrane. Exosomes function as cargo to deliver signaling molecules to distant cells. This allows cross-talk between hematopoietic cells and other distant target cell environments. Exosomes support leukemia growth by acting as messengers between tumor cells and the microenvironment as well as inducing oncogenic factors such as c-Myc. Exosomes have also been used as biomarkers in the clinical diagnosis of leukemia. Glycogen synthase kinase-3 (GSK-3) and protein phosphatase 2A (PP2A) are two crucial signaling molecules involved in the AML pathogenesis and MYC stability. GSK-3 is a serine/threonine protein kinase that coordinates with over 40 different proteins during physiological/pathological conditions in blood cells. The dysregulation in GSK-3 has been reported during hematological malignancies. GSK-3 acts as a tumor suppressor by targeting c-MYC, MCL-1 and β-catenin. Conversely, GSK-3 can also act as tumor promoter in some instances. The pharmacological modulators of GSK-3 such as ABT-869, 6-Bromoindirubin-3'-oxime (BIO), GS-87 and LY2090314 have shown promise in the treatment of hematological malignancy. PP2A is a heterotrimeric serine/threonine phosphatase involved in the regulation of hematological malignancy. PP2A-activating drugs (PADs) can effectively antagonize leukemogenesis. The discovery of exosomes, kinase inhibitors and phosphatase activators have provided new hope to the leukemia patients. This review discusses the role of exosomes, GSK-3 and PP2A in the pathogenesis of leukemia. We provide evidence from both preclinical and clinical studies., (Copyright © 2019. Published by Elsevier Ltd.)

Poor response to cancer therapy due to resistance remains a clinical challenge. The present study establishes a widely prevalent mechanism of resistance to gemcitabine in pancreatic cancer, whereby increased glycolytic flux leads to glucose addiction in cancer cells and a corresponding increase in pyrimidine biosynthesis to enhance the intrinsic levels of deoxycytidine triphosphate (dCTP). Increased levels of dCTP diminish the effective levels of gemcitabine through molecular competition. We also demonstrate that MUC1-regulated stabilization of hypoxia inducible factor-1α (HIF-1α) mediates such metabolic reprogramming. Targeting HIF-1α or de novo pyrimidine biosynthesis, in combination with gemcitabine, strongly diminishes tumor burden. Finally, reduced expression of TKT and CTPS, which regulate flux into pyrimidine biosynthesis, correlates with better prognosis in pancreatic cancer patients on fluoropyrimidine analogs., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Investigating BRAF((V600E)) inhibitors (BRAFi) as a strategy to treat patients with aggressive thyroid tumors harboring the BRAF((V600E)) mutant currently is in progress, and drug resistance is expected to pose a challenge. MicroRNAs (miRNAs) are involved in development of resistance to a variety of drugs in different malignancies., Methods: miRNA expression profiles in the human anaplastic thyroid cancer cell line (8505c) were compared with its PLX4720-resistant counterpart (8505c-R) by the use of Illumina deep sequencing. We conducted a functional annotation and pathway analysis of the putative and experimentally validated target genes of the significantly altered miRNAs., Results: We identified 61 known and 2 novel miRNAs whose expression was altered greatly in 8505c-R. Quantitative reverse-transcription polymerase chain reaction validated altered expression of 7 selected miRNAs in 8505c-R and BCPAP-R (PLX4720-resistant papillary thyroid cancer cell line). We found 14 and 25 miRNAs whose expression levels changed substantially in 8505c and 8505c-R, respectively, after treatment with BRAFi. The mitogen-activated protein kinase and phosphatidylinositol 3-kinase-AKT pathways were among the prominent targets of many of the deregulated miRNAs., Conclusion: We have identified a number of miRNAs that could be used as biomarkers of resistance to BRAFi in patients with thyroid cancer. In addition, these miRNAs can be explored as potential therapeutic targets in combination with BRAFi to overcome resistance., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Current treatment for recurrent and aggressive/anaplastic thyroid cancers is ineffective. Novel targeted therapies aimed at the inhibition of the mutated oncoprotein BRAF(V600E) have shown promise in vivo and in vitro but do not result in cellular apoptosis. TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in a tumor-selective manner by activating the extrinsic apoptotic pathway. Here, we show that a TRAIL-R2 agonist antibody, lexatumumab, induces apoptosis effectively in some thyroid cancer cell lines (HTh-7, TPC-1 and BCPAP), while more aggressive anaplastic cell lines (8505c and SW1736) show resistance. Treatment of the most resistant cell line, 8505c, using lexatumumab in combination with the BRAF(V600E) inhibitor, PLX4720, and the PI3K inhibitor, LY294002, (triple-drug combination) sensitizes the cells by triggering both the extrinsic and intrinsic apoptotic pathways in vitro as well as 8505c orthotopic thyroid tumors in vivo. A decrease in anti-apoptotic proteins, pAkt, Bcl-xL, Mcl-1 and c-FLIP, coupled with an increase in the activator proteins, Bax and Bim, results in an increase in the Bax to Bcl-xL ratio that appears to be critical for sensitization and subsequent apoptosis of these resistant cells. Our results suggest that targeting the death receptor pathway in thyroid cancer can be a promising strategy for inducing apoptosis in thyroid cancer cells, although combination with other kinase inhibitors may be needed in some of the more aggressive tumors initially resistant to apoptosis.