Abstract C54: Combination of PARP inhibitor talazoparib with etirinotecan pegol exhibits synergistic anti-tumor effect in non-BRCA preclinical cancer models

Author(s):  
Ying Feng ◽  
Yuqiao (Jerry) Shen ◽  
Leonard E. Post ◽  
Steve Doberstein ◽  
Deborah Charych ◽  
...  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Hyoung Kim ◽  
Haineng Xu ◽  
Erin George ◽  
Dorothy Hallberg ◽  
Sushil Kumar ◽  
...  

Author(s):  
Shifalika Tangutoori ◽  
Paige Baldwin ◽  
Jamie Medina ◽  
Anders Ohman ◽  
Daniela Dinulescu ◽  
...  

2020 ◽  
Author(s):  
Amanpreet Kaur ◽  
Sugunavathi Sepramaniam ◽  
Jun Yi Stanley Lim ◽  
Siddhi Patnaik ◽  
Nathan Harmston ◽  
...  

ABSTRACTWnt signaling maintains diverse adult stem cell compartments and is implicated in chemotherapy resistance in cancer. PORCN inhibitors that block Wnt secretion have proven effective in Wnt-addicted preclinical cancer models and are in clinical trials. In a survey for potential combination therapies, we found that Wnt inhibition synergizes with the PARP inhibitor olaparib in Wnt-addicted cancers. Mechanistically, we find that multiple genes in the homologous recombination and Fanconi anemia repair pathways, including BRCA1, FANCD2, and RAD51 are dependent on Wnt/β-catenin signaling in Wnt-high cancers, and treatment with a PORCN inhibitor creates a BRCA-like state. This coherent regulation of DNA repair genes occurs via a Wnt/β-catenin/MYBL2 axis. Importantly, this pathway also functions in intestinal crypts, where high expression of BRCA and Fanconi anemia genes is seen in intestinal stem cells, with further upregulation in Wnt high APCmin mutant polyps. Our findings suggest a general paradigm that Wnt/β-catenin signaling enhances DNA repair in stem cells and cancers to maintain genomic integrity. Conversely, interventions that block Wnt signaling may sensitize cancers to radiation and other DNA damaging agents.


2019 ◽  
Vol 476 (24) ◽  
pp. 3705-3719 ◽  
Author(s):  
Avani Vyas ◽  
Umamaheswar Duvvuri ◽  
Kirill Kiselyov

Platinum-containing drugs such as cisplatin and carboplatin are routinely used for the treatment of many solid tumors including squamous cell carcinoma of the head and neck (SCCHN). However, SCCHN resistance to platinum compounds is well documented. The resistance to platinum has been linked to the activity of divalent transporter ATP7B, which pumps platinum from the cytoplasm into lysosomes, decreasing its concentration in the cytoplasm. Several cancer models show increased expression of ATP7B; however, the reason for such an increase is not known. Here we show a strong positive correlation between mRNA levels of TMEM16A and ATP7B in human SCCHN tumors. TMEM16A overexpression and depletion in SCCHN cell lines caused parallel changes in the ATP7B mRNA levels. The ATP7B increase in TMEM16A-overexpressing cells was reversed by suppression of NADPH oxidase 2 (NOX2), by the antioxidant N-Acetyl-Cysteine (NAC) and by copper chelation using cuprizone and bathocuproine sulphonate (BCS). Pretreatment with either chelator significantly increased cisplatin's sensitivity, particularly in the context of TMEM16A overexpression. We propose that increased oxidative stress in TMEM16A-overexpressing cells liberates the chelated copper in the cytoplasm, leading to the transcriptional activation of ATP7B expression. This, in turn, decreases the efficacy of platinum compounds by promoting their vesicular sequestration. We think that such a new explanation of the mechanism of SCCHN tumors’ platinum resistance identifies novel approach to treating these tumors.


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