Elucidating mechanisms of chemoresistance is critical to improve cancer therapy, 
especially for the treatment of pancreatic ductal adenocarcinoma (PDAC). 
Genome-wide association studies have suggested the less studied gene HEAT 
repeat-containing protein 1 (HEATR1) as a possible determinant of cellular 
sensitivity to different chemotherapeutic drugs. In this study, we assessed this 
hypothesized link in PDAC, where HEATR1 expression is downregulated 
significantly. HEATR1 silencing in PDAC cells increased resistance to 
gemcitabine and other chemotherapeutics, where this effect was associated with 
increased AKT kinase phosphorylation at the Thr308 regulatory site. 
Mechanistically, HEATR1 enhanced cell responsiveness to gemcitabine by acting as 
a scaffold to facilitate interactions between AKT and the protein phosphatase 
PP2A, thereby promoting Thr308 dephosphorylation. Consistent with these 
findings, treatment with the AKT inhibitor triciribine sensitized 
HEATR1-depleted PDAC cells to gemcitabine, suggesting that this therapeutic 
combination may overcome gemcitabine resistance in patients with low HEATR1 
expression. Clinically, we found that HEATR1 downregulation in PDAC patients was 
associated with increased AKT phosphorylation, poor response to tumor resection 
plus gemcitabine standard-of-care treatment, and shorter overall survival. 
Collectively, our findings establish HEATR1 as a novel regulator of AKT and a 
candidate predictive and prognostic indicator of drug responsiveness and outcome 
in PDAC patients.