RESUMO
Because of essential roles of DNA damage response (DDR) in the maintenance of genomic integrity, cellular homeostasis, and tumor suppression, targeting DDR has become a promising therapeutic strategy for cancer treatment. However, the benefits of cancer therapy targeting DDR are limited mainly due to the lack of predictive biomarkers. To address this challenge, we performed CRISPR screens to search for genetic vulnerabilities that affect cells' response to DDR inhibition. By undertaking CRISPR screens with inhibitors targeting key DDR mediators, i.e. ATR, ATM, DNAPK and CHK1, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Specifically, we identified YWHAE loss as a key determinant of sensitivity to CHK1 inhibition. We showed that KLHL15 loss protects cells from DNA damage induced by ATM inhibition. Moreover, we validated that APEX1 loss sensitizes cells to DNAPK inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that an ATM inhibitor plus a PARP inhibitor induced dramatic levels of cell death, probably through promoting apoptosis. Our results enhance the understanding of DDR pathways and will facilitate the use of DDR-targeting agents in cancer therapy.
Assuntos
Proteínas 14-3-3/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Quinase 1 do Ponto de Checagem/genética , Dano ao DNA/genética , Proteína Quinase Ativada por DNA/genética , Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Sistemas CRISPR-Cas/genética , Quinase 1 do Ponto de Checagem/antagonistas & inibidores , Instabilidade Genômica/genética , Humanos , Proteínas dos Microfilamentos/genética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologiaRESUMO
Cancer-related diseases represent the second overall cause of death worldwide. Human papilloma virus (HPV) is an infectious agent which is mainly sexually transmitted and may lead to HPV-associated cancers in both men and women. Almost all cervical cancers are HPV-associated, however, an increasing number of head and neck cancers (HNCs), especially oropharyngeal cancer, can be linked to HPV infection. Moreover, anogenital cancers, including vaginal, vulvar, penial, and anal cancers, represent a subset of HPV-related cancers. Whereas testing and prevention of cervical cancer have significantly improved over past decades, anogenital cancers remain more difficult to confirm. Current clinical trials including patients with HPV-related cancers focus on finding proper testing for all HPV-associated cancers as well as improve the currently applied treatments. The HPV viral oncoproteins, E6 and E7, lead to degradation of, respectively, p53 and pRb resulting in entering the S phase without G1 arrest. These high-risk HPV viral oncogenes alter numerous cellular processes, including DNA repair, angiogenesis, and/or apoptosis, which eventually result in carcinogenesis. Additionally, a comprehensive analysis of gene expression and alteration among a panel of DNA double strand breaks (DSB) repair genes in HPV-negative and HPV-positive HNC cancers reveals differences pointing to HPV-dependent modifications of DNA repair processes in these cancers. In this review, we discuss the current knowledge regarding HPV-related cancers, current screening, and treatment options as well as DNA damage response-related biological aspects of the HPV infection and clinical trials.
