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Identification of resistance pathways specific to malignancy using organoid models of pancreatic cancer
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2019 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 25, no 22, p. 6742-6755Article in journal (Refereed) Published
Abstract [en]

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. In addition, 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.

Place, publisher, year, edition, pages
American Association for Cancer Research Inc. , 2019. Vol. 25, no 22, p. 6742-6755
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-170764DOI: 10.1158/1078-0432.CCR-19-1398ISI: 000497334300022PubMedID: 31492749Scopus ID: 2-s2.0-85075090376OAI: oai:DiVA.org:umu-170764DiVA, id: diva2:1430420
Funder
Swedish Research Council, 537-2013-7277Available from: 2020-05-14 Created: 2020-05-14 Last updated: 2023-08-25Bibliographically approved

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Öhlund, Daniel

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CiteExportLink to record
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Citation style
  • apa
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  • de-DE
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