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Effects of ATR inhibition in the sensitivity of HPV +/- tumor cells to cisplatin

Grant number: 17/12338-7
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): August 01, 2017
Effective date (End): July 31, 2020
Field of knowledge:Biological Sciences - Genetics
Principal Investigator:Carlos Frederico Martins Menck
Grantee:Eduardo Padilha Antonio
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:14/15982-6 - Consequences of repair deficiencies in damaged genome, AP.TEM

Abstract

Cervical cancer is one of the main types of cancer among women, and is responsible for about 4% of the cancer-related deaths worldwide. Since 1970 there has been increasing evidence of the association between this cancer and the infection by the Human Papillomavirus (HPV), which is responsible for 99,7% of the tumors. Of the types of HPV, the 16 and 18 are among the ones considered as high oncogenic risk, a characteristic they have due to the viral genes E6 and E7 which mediate de degradation of the cellular proteins p53 and pRb, respectively. The treatment usually involves Cisplatin, a DNA alkylating chemotherapeutic agent with high toxicity. The ATR kinase (ataxia-telangiectasia mutated (ATM) e RAD3-related kinase) is an essential enzyme for the replicative viability of human cells and its activation is specially related to the presence of single-stranded DNA, formed during the repair and replication processes of the damaged DNA. It also phosphorylates a series of substrates, among which the CHK1 protein, responsible for triggering a cascade effect which prevents cell cycle progression to mitosis. The treatment with the specific ATR inhibitor Ve-821 has been demonstrated capable of sensitizing cancer cells to ionizing radiation and different chemotherapies. This property is especially interesting to reduce the toxicity of the current treatments and overcome tumor resistance. Thus, this project intends to evaluate the synergistic effect between cellular transformation by HPV and the inhibition of the ATR kinase, combined with the cisplatin treatment, expecting to better understand the mechanisms of this effect and to obtain perspectives for the therapeutic protocol of these tumors. (AU)