Breast cancer is one of the leading causes of death in women in the United States. In general, patients with breast cancer undergo surgical resection of the tumor and/or receive drug treatment to kill or suppress the growth of cancer cells. In this regard, small molecule kinase inhibitors serve as an important class of drugs used in clinical and research settings. However, the development of resistance to these compounds, in particular HER2 and CDK4/6 inhibitors, often limits durable clinical responses to therapy. Emerging evidence indicates that PI3K/AKT/mTOR pathway hyperactivation is one of the most prominent mechanisms of resistance to many small molecule inhibitors as it bypasses upstream growth factor receptor inhibition. Importantly, the PI3K/AKT/mTOR pathway also plays a pertinent role in regulating various aspects of cancer metabolism. Recent studies from our lab and others have demonstrated that altered lipid metabolism mediates the development of acquired drug resistance to HER2-targeted therapies in breast cancer, raising an interesting link between reprogrammed kinase signaling and lipid metabolism. It appears that, upon development of resistance to HER2 inhibitors, breast cancer cells rewire lipid metabolism to somehow circumvent the inhibition of kinase signaling. Here, we review various mechanisms of resistance observed for kinase inhibitors and discuss lipid metabolism as a potential therapeutic target to overcome acquired drug resistance.
DNA topoisomerase I enzymes relieve the torsional strain in DNA; they are essential for fundamental molecular processes such as DNA replication, transcription, recombination, and chromosome condensation; and act by cleaving and then religating DNA strands. Over the past few decades, scientists have focused on the DNA topoisomerases biological functions and established a unique role of Type I DNA topoisomerases in regulating gene expression and DNA chromosome condensation. Moreover, the human enzyme is being investigated as a target for cancer chemotherapy. The active site tyrosine is responsible for initiating two transesterification reactions to cleave and then religate the DNA backbone, allowing the release of superhelical tension. The different steps of the catalytic mechanism are affected by various inhibitors; some of them prevent the interaction between the enzyme and the DNA while others act as poisons, leading to TopI-DNA lesions, breakage of DNA, and eventually cellular death. In this review, our goal is to provide an overview of mechanism of human topoisomerase IB action together with the different types of inhibitors and their effect on the enzyme functionality.
Cancer is the second leading cause of death worldwide. The survival of cancer patients depends on the efficacy of therapies and the development of resistance. There are many mechanisms involved in the acquisition of drug resistance by cancer cells, including the acquisition of stem-like features. Cancer stem cells (CSCs) represent a major source of tumor progression and treatment resistance. CSCs are a subpopulation of cancer cells having the abilities to self-renew and form spheres in vitro. Aldehyde dehydrogenase 1A1 (ALDH1A1) is a cytosolic enzyme involved in the detoxification of cells from toxic aldehydes and belongs to the ALDH family. High ALDH1A1 activity is closely related to stemness phenotype of several tumors, possibly contributing to cancer progression and diffusion in the body. We have documented the contribution of ALDH1A1 in tumor angiogenesis in breast cancer cells by the activation of hypoxia inducible factor-1α and vascular endothelial growth factor signaling. This review discusses the involvement of ALDH1A1 in the development of different hallmarks of cancer to propose it as a novel putative target for cancer treatment to achieve better outcome. Here, we analyze the involvement of ALDH1A1 in the acquisition of stemness phenotype in tumor cells, the regulation of tumor angiogenesis and metastases, and the acquisition of anticancer drug resistance and immune evasion.
Epithelial-mesenchymal transition (EMT) and autophagy are both known to play important roles in the development of cancer. Subsequently, these processes are now being utilised as targets for therapy. Cancer is globally one of the leading causes of death, and, despite many advances in treatment options, patients still face many challenges. Drug resistance in cancer-therapy is a large problem, and both EMT and autophagy have been shown to contribute. However, given the context-dependent role of these processes and the complexity of the interactions between them, elucidating how they both act alone and interact is important. In this review, we provide insight into the current landscape of the interactions of autophagy and EMT in the context of malignancy, and how this ultimately may affect drug resistance in cancer therapy.
Cyclin-dependent kinases (CDKs) are important regulatory enzymes in the normal physiological processes that drive cell-cycle transitions and regulate transcription. Virtually all cancers harbour genomic alterations that lead to the constitutive activation of CDKs, resulting in the proliferation of cancer cells. CDK inhibitors (CKIs) are currently in clinical use for the treatment of breast cancer, combined with endocrine therapy. In this review, we describe the potential of CKIs for the treatment of cancer with specific focus on glioblastoma (GBM), the most common and aggressive primary brain tumour in adults. Despite intense effort to combat GBM with surgery, radiation and temozolomide chemotherapy, the median survival for patients is 15 months and the majority of patients experience disease recurrence within 6-8 months of treatment onset. Novel therapeutic approaches are urgently needed for both newly diagnosed and recurrent GBM patients. In this review, we summarise the current preclinical and clinical findings emphasising that CKIs could represent an exciting novel approach for GBM treatment.
Exosomes are small extracellular vesicles engaged in intercellular communication in both healthy and tumor cells. When released by the primary tumor, they transfer their cargo including nucleic acids, proteins, and lipids to target cells, thus modulating the character and fate of the recipient cells. By propagating their oncogenic content, exosomes are able to promote tumor progression, angiogenesis, metastases, and drug resistance. Their functions as delivery vehicles of biological material make exosomes promising biomarkers for the early prediction of disease progression and drug resistance in breast cancer, as well as for therapeutic targeting of molecules to treat this deadly disease. In the present review, we accentuate the relevance of exosomes as vehicles of prognostic and predictive markers and target molecules, and describe their potential therapeutic applications as drug cargo suppliers. We made an extensive literature research to clarify the association of their cargo, including exosomal DNA and RNA molecules, with the propagation of drug resistance.
Aim: Previous studies suggest that circulating tumor cells (CTC) are present at very low frequencies in blood of pancreatic cancer (PC) patients. However, no technique has proven efficient for their detection, in part due to the lack of accurate tumor markers. Here, we evaluated the potential utility of two marker candidates - Mucin 16 (MUC16) and Tetraspanin 1 (TSPAN1) - identified through a detailed review of the literature.
Methods: To evaluate the pattern of expression of both markers in pancreatic tumor cells vs. normal blood, we used cell lines derived from pancreatic cancer patients and blood from healthy adults.
Results: Antibodies against both MUC16 and TSPAN1 showed expression in three pancreatic cancer (PC) cell lines while they were absent in blood cells. To evaluate the efficiency of isolating tumor cells from blood, PC cell lines were spiked at different frequencies in blood, sequentially stained with biotin-conjugated TSPAN1 and MUC16 antibodies and a streptavidin ferrofluids, followed by immunomagnetic enrichment. The recovery of spiked TSPAN1+ tumor cells was high with limited contamination by leukocytes. In contrast, no PC cells were isolated when the biotin MUC16 reagent was used because the biotin-conjugated clone did not recognize PC cells.
Conclusion: The combination of MUC16, TSPAN1, and epithelial cell adhesion molecule (EpCAM) antibodies will likely increase the efficiency of capturing circulating tumor cell in blood of pancreatic ductal adenocarcinoma. To further develop a protocol for isolation of circulating tumor cell in blood of PC patients, high amounts of antibodies (5-10 mg) against EpCAM, MUC16, and TSPAN1 will be needed.
Aim: Different types of chronic medication may affect breast cancer prognosis. Circulating tumor cells (CTCs) play an important role in cancer metastasis formation. There is no evidence of how chronic medication affects CTCs and breast cancer prognosis. The aim of this study was to evaluate association between chronic medication and CTCs in patients with primary breast cancer.
Methods: This study involved 414 patients with stage I-III primary breast cancer. Chronic drug history was collected from patients’ medical records and included all drugs that were prescribed for patients over at least the last 6 months prior to CTCs evaluation. CTCs were detected using a quantitative real-time polymerase chain reaction (qRT-PCR)-based method at the time of breast surgery.
Results: There was no association between CTCs, including their different subpopulations and chronic medication. Chronic medication using angiotensin-converting-enzyme inhibitors (ACEi), metformin, and insulin were associated with inferior disease-free survival (HR = 0.49, 95%CI 0.26-0.94, P = 0.007 for ACEi; HR = 0.27, 95%CI 0.08-0.91, P < 0.001 for metformin; and HR = 0.12, 95%CI 0.01-2.91, P < 0.001 for insulin) and this was most pronounced in patients with epithelial to mesenchymal transition (CTC_EMT) phenotype. In multivariate analysis, chronic administration of metformin and/or insulin was an independent predictor of inferior outcome.
Conclusion: Our findings show that there was no association between chronically used medication and CTCs in primary breast cancer patients. However, administration of ACEi, metformin, and/or insulin could negatively affect prognosis of patients with CTC_EMT.