Mechanisms of tumor resistance to cisplatin: DNA lesions processing and circadian cycle effect

Abstract

Currently, Cancer is one of the main causes of morbidity and mortality worldwide, with approximately 14 million new cases in 2012 and 8.8 million Cancer-related deaths in 2015, in which 1.69 million were from Lung Cancer. This high index of mortality is mainly due to the shortage of treatments that provide a definitive cure, or even a longer life span. One of the most used treatments is the chemotherapy with cisplatin, based on the cytotoxicity caused by DNA damage induced by the drug. However, drug resistance is very common, due to alterations in the expression of genes that protect the cells. Among these alterations, the augmented expression of the proteins ERCC1 and XPF, components of the Nucleotide Excision Repair pathway (NER), and of the well-known master regulator of antioxidant response, the transcription factor NRF2, stand out as main causes of resistance in some cases. Some studies also show that the DNA polymerase eta, involved in translesion synthesis, may be important for the resistance to cisplatin. Interestingly, there is evidence that these processes are under control of the circadian clock, an internal timing mechanism, orchestrating variations in behavior, physiology and metabolism, according to daily changes in our environment such as temperature and light/dark cycles. Thus, this project aims to understand the role of each process mentioned above in the establishment of cisplatin resistance in Lung Cancer cells, how they interact and their effects. Furthermore, we want to understand how the circadian clock influences each of these processes and can be an important factor in the resistance to the treatment with cisplatin. (AU)