Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer

Ponz-Sarvise, M., Corbo, V., Tiriac, H., Engle, D. D., Frese, K. K., Oni, T. E., Hwang, C. I., Ohlund, D., Chio, I. I. C., Baker, L. A., Filippini, D., Wright, K., Bapiro, T. E., Huang, P. S., Smith, P. D., Yu, K. H., Jodrell, D. I., Park, Y., Tuveson, D. A. (September 2019) Identification of Resistance Pathways Specific to Malignancy Using Organoid Models of Pancreatic Cancer. Clin Cancer Res. ISSN 1078-0432 (Print)1078-0432

URL: https://www.ncbi.nlm.nih.gov/pubmed/31492749
DOI: 10.1158/1078-0432.ccr-19-1398

Abstract

PURPOSE: KRAS is mutated in the majority of pancreatic ductal adenocarcinoma. MAPK and PI3K-AKT are primary KRAS effector pathways, but combined MAPK and PI3K inhibition has not been demonstrated to be clinically effective to date. We explore the resistance mechanisms uniquely employed by malignant cells. EXPERIMENTAL DESIGN: We evaluated the expression and activation of receptor tyrosine kinases in response to combined MEK and AKT inhibition in KPC mice and pancreatic ductal organoids. Additionally, we sought to determine the therapeutic efficacy of targeting resistance pathways induced by MEK and AKT inhibition in order to identify malignant-specific vulnerabilities. RESULTS: Combined MEK and AKT inhibition modestly extended the survival of KPC mice and increased Egfr and ErbB2 phosphorylation levels. Tumor organoids, but not their normal counterparts, exhibited elevated phosphorylation of ERBB2 and ERBB3 after MEK and AKT blockade. A pan-ERBB inhibitor synergized with MEK and AKT blockade in human PDA organoids, whereas this was not observed for the EGFR inhibitor Erlotinib. Combined MEK and ERBB inhibitor treatment of human organoid orthotopic xenografts was sufficient to cause tumor regression in short-term intervention studies. CONCLUSIONS: Analyses of normal and tumor pancreatic organoids revealed the importance of ERBB activation during MEK and AKT blockade primarily in the malignant cultures. The lack of ERBB hyperactivation in normal organoids suggests a larger therapeutic index. In our models pan-ERBB inhibition was synergistic with dual inhibition of MEK and AKT and the combination of a pan-ERBB inhibitor with MEK antagonists showed the highest activity both in vitro and in vivo.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > Akt
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function > genes: types > ErbB
Investigative techniques and equipment > cell culture > cancer organoids
diseases & disorders > cancer > cancer types > pancreatic cancer
CSHL Authors:
Communities: CSHL labs > Tuveson lab
Depositing User: Matthew Dunn
Date: 6 September 2019
Date Deposited: 16 Sep 2019 15:55
Last Modified: 16 Sep 2019 15:55
Related URLs:
URI: http://repository.cshl.edu/id/eprint/38402

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