Role and Molecular Mechanism of Inhibitors in Cancers

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (15 May 2023) | Viewed by 2928

Special Issue Editor

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Guest Editor
Ontario Institute for Cancer Research, Toronto, ON, Canada
Interests: : cancer therapeutics; protein-protein interactions; cell signaling; WD repeat proteins; receptor tyrosine kinases

Special Issue Information

Dear Colleagues, 

Cancer is major global health burden requiring innovative therapeutic strategies to help to circumvent death. Traditional treatments include surgery and non-specific chemotherapy to reduce tumor burden. With recent advances in cancer genomics and proteomics, multiple driver oncogenes have been identified and targeted successfully, most notably members of the kinase family involved in various cell signaling events. Furthermore, advances in antibody and small-molecule-based drug discovery have led to the development of multiple inhibitors for various cancer-related proteins. Recent advances in cancer immunotherapy have also helped to provide patients with unique therapeutic options to treat multiple types of cancer. Going forward, the field of cancer therapeutics will need to heavily rely on individual patient tumor genomic and proteomic profiles to deduce which therapeutic regimens would be most effective in this era of personalized medicine.

This Special Issue will summarize the role and molecular mechanisms of currently available inhibitors involved in treating various types of cancers. The use of small molecules and biologics as potential therapies to prevent or treat the progression of cancer will also be addressed.

Dr. Punit Saraon
Guest Editor

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  • cancer
  • therapeutics
  • drug discovery
  • biomarkers
  • oncogenes
  • tumor suppressors
  • cell signaling
  • proteomics
  • antibodies
  • small molecules
  • kinase inhibitors
  • protein–protein interactions
  • immunotherapy
  • chemotherapy

Published Papers (1 paper)

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38 pages, 6004 KiB  
Olaparib-Resistant BRCA2MUT Ovarian Cancer Cells with Restored BRCA2 Abrogate Olaparib-Induced DNA Damage and G2/M Arrest Controlled by the ATR/CHK1 Pathway for Survival
by Łukasz Biegała, Arkadiusz Gajek, Agnieszka Marczak and Aneta Rogalska
Cells 2023, 12(7), 1038; - 29 Mar 2023
Cited by 6 | Viewed by 2519
The PARP inhibitor (PARPi) olaparib is currently the drug of choice for serous ovarian cancer (OC), especially in patients with homologous recombination (HR) repair deficiency associated with deleterious BRCA1/2 mutations. Unfortunately, OC patients who fail to respond to PARPi or relapse after treatment [...] Read more.
The PARP inhibitor (PARPi) olaparib is currently the drug of choice for serous ovarian cancer (OC), especially in patients with homologous recombination (HR) repair deficiency associated with deleterious BRCA1/2 mutations. Unfortunately, OC patients who fail to respond to PARPi or relapse after treatment have limited therapeutic options. To elucidate olaparib resistance and enhance the efficacy of olaparib, intracellular factors exploited by OC cells to achieve decreased sensitivity to PARPi were examined. An olaparib-resistant OC cell line, PEO1-OR, was established from BRCA2MUT PEO1 cells. The anticancer activity and action of olaparib combined with inhibitors of the ATR/CHK1 pathway (ceralasertib as ATRi, MK-8776 as CHK1i) in olaparib-sensitive and -resistant OC cell lines were evaluated. Whole-exome sequencing revealed that PEO1-OR cells acquire resistance through subclonal enrichment of BRCA2 secondary mutations that restore functional full-length protein. Moreover, PEO1-OR cells upregulate HR repair-promoting factors (BRCA1, BRCA2, RAD51) and PARP1. Olaparib-inducible activation of the ATR/CHK1 pathway and G2/M arrest is abrogated in olaparib-resistant cells. Drug sensitivity assays revealed that PEO1-OR cells are less sensitive to ATRi and CHK1i agents. Combined treatment is less effective in olaparib-resistant cells considering inhibition of metabolic activity, colony formation, survival, accumulation of DNA double-strand breaks, and chromosomal aberrations. However, synergistic antitumor activity between compounds is achievable in PEO1-OR cells. Collectively, olaparib-resistant cells display co-existing HR repair-related mechanisms that confer resistance to olaparib, which may be effectively utilized to resensitize them to PARPi via combination therapy. Importantly, the addition of ATR/CHK1 pathway inhibitors to olaparib has the potential to overcome acquired resistance to PARPi. Full article
(This article belongs to the Special Issue Role and Molecular Mechanism of Inhibitors in Cancers)
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