Abstract
Cancer is the second leading cause of death in the US. Current major treatments for cancer management include surgery, cytotoxic chemotherapy, targeted therapy, radiation therapy, endocrine therapy and immunotherapy. Despite the endeavors and achievements made in treating cancers during the past decades, resistance to classical chemotherapeutic agents and/or novel targeted drugs continues to be a major problem in cancer therapies. Drug resistance, either existing before treatment (intrinsic) or generated after therapy (acquired), is responsible for most relapses of cancer, one of the major causes of death of the disease. Heterogeneity among patients and tumors, and the versatility of cancer to circumvent therapies make drug resistance more challenging to deal with. Better understanding the mechanisms of drug resistance is required to provide guidance to future cancer treatment and achieve better outcomes. In this review, intrinsic and acquired resistance will be discussed. In addition, new discoveries in mechanisms of drug resistance will be reviewed. Particularly, we will highlight roles of ATP in drug resistance by discussing recent findings of exceptionally high levels of intratumoral extracellular ATP as well as intracellular ATP internalized from extracellular environment. The complexity of drug resistance development suggests that combinational and personalized therapies, which should take ATP into consideration, might provide better strategies and improved efficacy for fighting drug resistance in cancer.
Highlights
Cancer is the second leading cause of death in the US[1]
Drug resistance is induced at levels of DNA, RNA, and proteins [concentration and activity changes of receptor tyrosine kinases (RTK in general and epidermal growth factor receptor (EGFR) in specific, and ATP binding cassette (ABC) transporters)]
When studying ATP promoted drug resistance to sunitinib in non-small cell lung cancer (NSCLC) A549 cells, we found that extracellular ATP can be internalized by cancer cells through macropinocytosis and other endocytic mechanisms, resulting in substantially elevated intracellular ATP levels from 150 to 200% of the original intracellular ATP concentrations[161,179,180]
Summary
Cancer is the second leading cause of death in the US[1]. In 2017, about 1.7 million people were diagnosed with cancer and 0.6 million people died from the disease[2]. Acquired resistance can be a result of: (1) activation of second proto-oncogene that becomes the newly emerged driver gene; (2) mutations or altered expression levels of the drug targets; (3) changes in tumor microenvironment (TME) after treatment.
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