4.7 Article

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

Journal

CLINICAL CANCER RESEARCH
Volume 25, Issue 22, Pages 6742-6755

Publisher

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-19-1398

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Funding

  1. University of Cambridge and Cancer Research UK
  2. Li Ka Shing Foundation
  3. Hutchison Whampoa Limited
  4. NIHR Cambridge Biomedical Research Centre
  5. NIH Ruth L. Kirschstein National Research Service Award [F32CA123887-01]
  6. European Community [EPC-TM-Net 256974]
  7. Cancer Research UK
  8. Cancer Research UK Cambridge Research Institute
  9. Lustgarten Foundation
  10. Lustgarten Foundation-designated Laboratory of Pancreatic Cancer Research
  11. Cancer Center Support Grant [5P30CA045508]
  12. Cold Spring Harbor Laboratory Association
  13. Stand Up To Cancer Phillip A. Sharp Innovation in Collaboration Award [SU2C-AACR-PS09]
  14. Stand Up to Cancer is a division of the Entertainment Industry Foundation
  15. Cold Spring Harbor Laboratory
  16. STARR foundation [I7-A718]
  17. DOD [W81XWH-13-PRCRP-IA]
  18. Associazione Italiana Ricerca sul Cancro [AIRC-18718]
  19. Swedish Research Council [537-2013-7277]
  20. Kempe Foundations [JCK-1301]
  21. Swedish Society of Medicine [SLS326921, SLS-250831]
  22. Damon Runyon Cancer Research Foundation [DRG-2165-13]
  23. NIH [5P30CA45508-26, 5P50CA101955-07, 1U10CA180944-01, 5U01CA168409-3, 1R01CA19009201, 1R01CA188134-01A1, R50CA211506, F32CA180717, 5T32CA148056, 1K99CA204725-01A1, P50CA101955]
  24. UAB/UMN SPORE

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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 malignantspecific 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.

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