Ambar gris9/18/2023 ![]() Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models.Īlthough WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. Biomarker analysis was conducted at the genetic and protein level. ![]() We analyzed breast and ovarian patient-derived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. 14 High Risk and Familial Cancer, Vall d'Hebron Institute of Oncology, Barcelona, Spain.13 Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.12 Department of Cell Development and Cancer Biology, Knight Cancer Institute, Oregon Health and Sciences University, Portland, Oregon.11 Breast Cancer and Melanoma Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.10 Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.9 Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.8 Growth Factors Laboratory, Vall d'Hebron Institute of Oncology, Barcelona, Spain.7 Cancer Research UK, Cambridge Institute, Cambridge, United Kingdom.6 The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom. ![]()
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