Combined Arsenic Trioxide With BET Brodomain Inhibitor Suppress Pdac Via Targeting The NRF2-mediated Autophagy Regulatory Circuitry

Pancreatic cancer is one of the most aggressive malignancies in humans and in the past two decades the 5-year survival rate has been only 5%.Pancreatic ductal adenocarcinoma(PDAC)is the most common form of human pancreatic cancer,accounting for more than 95% of all cases,and almost all patients with PDAC die from metastasis.Mutations in the KRAS and P53 genes have been considered the driving events and the most common mutations in PDACs;however,targeting the mutated KRAS and P53 genes has proven to be challenging.There is an urgent need to identify new and common cellular vulnerabilities in pancreatic cancer cells and to identify new(innovative)mechanism-based therapeutic goals and strategies.Recent studies have found that high levels of autophagy are required for tumorigenesis of PDAC..Endoplasmic reticulum stress response is considered to be an important stimulus for autophagy.In this issue,we sought to find out the molecular mechanisms that cause pancreatic cancer to develop resistance to oxidative stress drugs and try to find new treatments,providing a new strategy for the clinical treatment of pancreatic cancer.First,we used arsenic trioxide,an endoplasmic reticulum stress response and an oxidativestress inducer,to treat 11 pancreatic ductal adenocarcinoma cell lines and found that they were not equally sensitive to arsenic trioxide.Only two of the cell lines,BXPC-3 and MIAPACA2,are highly sensitive to arsenic trioxide,nine other cells showed varying degrees of resistance to arsenic trioxide.Capan1 and HUP-T4 showed moderate sensitivity to arsenic trioxide.Seven strains of CFPac-1,SW1990,ASPC-1,QGP-1,PANC-1,HPAF-II and YAPC were highly insensitive to arsenic trioxide.Further through microarray data analysis found that arsenic trioxide treatment of sensitive cells BXPC-3 and MIAPCA mainly by inducing autophagic cell death to cause cell death.However,there was no change in autophagy related markers in drug-resistant cells.Further bioinformatics analysis found that in drug-resistant cells,the addition of arsenic trioxide make the cell resistant by stimulating the activation of intracellular NRF2 signaling,whereas NRF2 directly regulates the expression of autophagy-related genes in cells and thus inhibits autophagic cell death.Inhibition of drug-resistant intracellular NRF2 signaling pathway activation,then add arsenic trioxide treatment,cell resistance will be reduced.Endoplasmic reticulum stress response-related indicators have also been increased,while autophagy-related indicators and core regulatory gene set also occurred.Next,we sought to find small molecule drugs that could inhibit the activation of the NRF2 signaling pathway in drug-resistant cells in an attempt to produce a combination effect with arsenic trioxide.Our study found that BET brodomain small molecule inhibitor of protein JQ1 and arsenic trioxide can produce better combination effect.In the arsenic trioxide-resistant cell line,JQ1 primarily achieves cell death by mediating autophagy by enhancing endoplasmic reticulum stress induced by arsenic trioxide.Moreover,JQ1 can inhibit the activation of arsenic trioxide-induced NRF2 signaling pathway.In summary,through the study of this topic,we found the molecular mechanism of pancreatic cancer cells resistance to oxidative stress drugs,and found a small molecule inhibitor which could produce combined drug effects with oxidative stress drugs,will be for clinical treatment Pancreatic cancer offers new therapeutic strategies.