ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias

BOUDNÝ, Miroslav and Martin TRBUŠEK. ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias. CANCER TREATMENT REVIEWS. OXFORD: ELSEVIER SCI LTD, vol. 88, AUG, p. 102026-102037. ISSN 0305-7372. doi:10.1016/j.ctrv.2020.102026. 2020.

Basic information

• Original name: ATR-CHK1 pathway as a therapeutic target for acute and chronic leukemias
• Authors: BOUDNÝ, Miroslav (203 Czech Republic, guarantor, belonging to the institution) and Martin TRBUŠEK (203 Czech Republic, belonging to the institution).
• Edition: CANCER TREATMENT REVIEWS, OXFORD, ELSEVIER SCI LTD, 2020, 0305-7372.

Other information

• Original language: English
• Type of outcome: Article in a journal
• Field of Study: 30204 Oncology
• Country of publisher: United Kingdom of Great Britain and Northern Ireland
• Confidentiality degree: is not subject to a state or trade secret
• WWW: URL
• Impact factor: Impact factor: 12.111
• RIV identification code: RIV/00216224:14740/20:00117585
• Organization unit: Central European Institute of Technology
• Doi: http://dx.doi.org/10.1016/j.ctrv.2020.102026
• UT WoS: 000550255600002
• Keywords in English: DDR; ATR; CHK1; Inhibition; Leukemia
• Tags: 14110212, podil, rivok
• Tags: International impact, Reviewed

Abstract

Progress in cancer therapy changed the outcome of many patients and moved therapy from chemotherapy agents to targeted drugs. Targeted drugs already changed the clinical practice in treatment of leukemias, such as imatinib (BCR/ABL inhibitor) in chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL), ibrutinib (Bruton's tyrosine kinase inhibitor) in chronic lymphocytic leukemia (CLL), venetoclax (BCL2 inhibitor) in CLL and acute myeloid leukemia (AML) or midostaurin (FLT3 inhibitor) in AML. In this review, we focused on DNA damage response (DDR) inhibition, specifically on inhibition of ATR-CHK1 pathway. Cancer cells harbor often defects in different DDR pathways, which render them vulnerable to DDR inhibition. Some DDR inhibitors showed interesting single-agent activity even in the absence of cytotoxic drug especially in cancers with underlying defects in DDR or DNA replication. Almost no mutations were found in ATR and CHEK1 genes in leukemia patients. Together with the fact that ATR-CHK1 pathway is essential for cell development and survival of leukemia cells, it represents a promising therapeutic target for treatment of leukemia. ATR-CHK1 inhibition showed excellent results in preclinical testing in acute and chronic leukemias. However, results in clinical trials are so far insufficient. Therefore, the ongoing and future clinical trials will decide on the success of ATR/CHK1 inhibitors in clinical practice of leukemia treatment.

Links

• LQ1601, research and development project: Name: CEITEC 2020 (Acronym: CEITEC2020)

Investor: Ministry of Education, Youth and Sports of the CR

• NV15-33999A, research and development project: Name: Vývoj nových nízkomolekulárních protinádorových léčiv na principu syntetické letality
• NV16-32743A, research and development project: Name: Prediktivní stratifikace pacientů s CLL pro terapie využívající monoklonální protilátky cílené na antigen CD20