Pancreatic ductal adenocarcinoma (PDA) is a lethal disease with a 5-year survival rate less than 6%. Novel models of PDA able of predicting resistance/sensitivity to treatment are needed. Our lab has developed a 3D culture system that enables the growth, as organoids, of both mouse and human pancreatic ducts. These organoids can be established either from healthy or neoplastic tissues, providing a platform for the therapeutics.
We used the organoids to evaluate the therapeutic efficacy of the simultaneous inhibition of the kinases MEK1/2 and AKTs. Toxicity was assessed in vitro by measuring ATP content in mouse and human organoids treated with single agents or combination for 72hrs. Genetically engineered mice developing pancreatic cancer (KPC) were used for the in vivo study.KPC were randomly assigned to different treatment arms and then treated.
The dual inhibition of MEK1/2 and AKTs, combined with the cytotoxic drug gemcitabine, provided the longest extension in median survival, but without preventing mice to succumb of their disease. Tumor-derived organoids were highly resistant to both single agents and combination. To assess the potential mechanism of resistance we evaluated the activation of a number of receptor tyrosine kinases (RTKs) by interrogating KPC treated tissues. Members of the ERBB family were activated in mice treated with the combination compared to those treated with gemcitabine only. Accordingly, we analyzed the expression and activation of several RTKs, including the ERBB family, at baseline and after treatment in both mouse and human organoids. Dual inhibition of MEK1/2 and AKTs induced changes in the expression of ERBB receptors and ligands in both normal and tumor-derived organoids. However, only tumor organoids showed a significant increase in the expression and activation of receptors upon treatment that was accompanied by the re-activation of ERK and AKT. Accordingly, the addition of an irreversible pan-ERBB inhibitor to the combination of MEK1/2 and AKTs prevented the rewiring of the pathways and improved tumor sensitivity.
Pancreatic organoids represent a system that can be used to predict drug sensitivity as well as to identify mechanism of resistance.
Clinical trial identification
Legal entity responsible for the study
Cold Spring Harbor Laboratory
All authors have declared no conflicts of interest.