Identification of resistance pathways specific to malignancy using organoid models of pancreatic cancer
Frese, Kristopher K
AffiliationMedical Oncology, Clinica Universidad de Navarra, Universidad de Navarra
MetadataShow full item record
AbstractPURPOSE: 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.
CitationPonz-Sarvise M, Corbo V, Tiriac H, Engle DD, Frese KK, Oni TE, et al. Identification of resistance pathways specific to malignancy using organoid models of pancreatic cancer. Clin Cancer Res. 2019 Sep 6.
JournalClinical Cancer Research
- Co-treatment with panitumumab and trastuzumab augments response to the MEK inhibitor trametinib in a patient-derived xenograft model of pancreatic cancer.
- Authors: Lindberg JM, Newhook TE, Adair SJ, Walters DM, Kim AJ, Stelow EB, Parsons JT, Bauer TW
- Issue date: 2014 Jul
- Upstream and Downstream Co-inhibition of Mitogen-Activated Protein Kinase and PI3K/Akt/mTOR Pathways in Pancreatic Ductal Adenocarcinoma.
- Authors: Wong MH, Xue A, Baxter RC, Pavlakis N, Smith RC
- Issue date: 2016 Jul
- Cotargeting of epidermal growth factor receptor and PI3K overcomes PI3K-Akt oncogenic dependence in pancreatic ductal adenocarcinoma.
- Authors: Wong MH, Xue A, Julovi SM, Pavlakis N, Samra JS, Hugh TJ, Gill AJ, Peters L, Baxter RC, Smith RC
- Issue date: 2014 Aug 1
- Synergistic effects of concurrent blockade of PI3K and MEK pathways in pancreatic cancer preclinical models.
- Authors: Zhong H, Sanchez C, Spitzer D, Plambeck-Suess S, Gibbs J, Hawkins WG, Denardo D, Gao F, Pufahl RA, Lockhart AC, Xu M, Linehan D, Weber J, Wang-Gillam A
- Issue date: 2013
- Hypoxia increases resistance of human pancreatic cancer cells to apoptosis induced by gemcitabine.
- Authors: Yokoi K, Fidler IJ
- Issue date: 2004 Apr 1