Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Introduction: Molecular analyzes including molecular descriptor/phenotype interactions have led to better characterization of epithelial ovarian cancer patients, including a definition of a BRCA wild-type (BRCAwt) phenotype. Understanding how and when to use agents targeted against dependent BRCAwt pathways or other molecular events at disease progression is an important translational and therapeutic direction in ovarian cancer research. Areas covered: In this overview, we provide definitions and descriptions of a BRCAwt genotype and phenotype. We discuss novel investigational drugs that hold promise for the treatment of BRCAwt ovarian cancer, including inhibitors of poly(ADP-ribose) polymerase, ribonucleotide reductase, DNA protein kinase-catalytic subunit, ataxia-telangiectasia-mutated kinase (ATM), ataxia-telangiectasia mutated and Rad3-related kinase (ATR), CHK 1/2, cyclin kinases, glutaminase-1, WEE1 kinase, as well as tumor microenvironment and angiogenesis inhibitors. This article explores the known and the emerging areas of clinical research on patients with BRCAwt ovarian cancer. Expert opinion: Discovery of molecular changes tied to annotated disease information, along with an expanding array of pathway targets and targeted therapeutic agents, creates optimism and opportunity for women with ovarian cancer. Using precision oncology approaches, clinical researchers are, and will be, poised to select more effective treatments for ovarian cancer patients.
 ...
PMID:Defining and targeting wild-type BRCA high-grade serous ovarian cancer: DNA repair and cell cycle checkpoints. 3144 60

Inhibition of ribonucleotide reductase (RNR), the rate-limiting enzyme in the synthesis of deoxyribonucleotides, causes DNA replication stress and activates the ataxia telangiectasia and rad3-related protein (ATR)-checkpoint kinase 1 (CHK1) pathway. Notably, a number of different cancers, including Ewing sarcoma tumors, are sensitive to the combination of RNR and ATR-CHK1 inhibitors. However, multiple, overlapping mechanisms are reported to underlie the toxicity of ATR-CHK1 inhibitors, both as single agents and in combination with RNR inhibitors, toward cancer cells. Here, we identified a feedback loop in Ewing sarcoma cells in which inhibition of the ATR-CHK1 pathway depletes RRM2, the small subunit of RNR, and exacerbates the DNA replication stress and DNA damage caused by RNR inhibitors. Mechanistically, we identified that the inhibition of ATR-CHK1 activates CDK2, which targets RRM2 for degradation via the proteasome. Similarly, activation of CDK2 by inhibition or knockdown of the WEE1 kinase also depletes RRM2 and causes DNA damage and apoptosis. Moreover, we show that the concurrent inhibition of ATR and WEE1 has a synergistic effect in Ewing sarcoma cells. Overall, our results provide novel insight into the response to DNA replication stress, as well as a rationale for targeting the ATR, CHK1, and WEE1 pathways, in Ewing sarcoma tumors. IMPLICATIONS: Targeting the ATR, CHK1, and WEE1 kinases in Ewing sarcoma cells activates CDK2 and increases DNA replication stress by promoting the proteasome-mediated degradation of RRM2.
 ...
PMID:Inhibition of the ATR-CHK1 Pathway in Ewing Sarcoma Cells Causes DNA Damage and Apoptosis via the CDK2-Mediated Degradation of RRM2. 3164 26


<< Previous 1 2 3