MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, su...

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Veröffentlicht in:Oncogene Jg. 39; H. 8; S. 1821 - 1829
Hauptverfasser: Castillo, Lesley, Young, Adelaide I J, Mawson, Amanda, Schafranek, Pia, Steinmann, Angela M, Nessem, Danielle, Parkin, Ashleigh, Johns, Amber, Chou, Angela, Law, Andrew M K, Lucas, Morghan C, Murphy, Kendelle J, Deng, Niantao, Gallego-Ortega, David, Caldon, Catherine E, Timpson, Paul, Pajic, Marina, Ormandy, Christopher J, Oakes, Samantha R
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England Nature Publishing Group 01.02.2020
Schlagworte:
Adenocarcinoma
Adenocarcinoma - pathology
Animal models
Cell culture
Cell Line, Tumor
Cell viability
Cytoskeleton
Dasatinib - pharmacology
Drug Synergism
Enzyme inhibitors
Gene expression
Genomes
Humans
Immunohistochemistry
Invasiveness
Liver cancer
Mcl-1 protein
Metastases
Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors
Neoplasm Invasiveness
Pancreatic cancer
Pancreatic Neoplasms - pathology
Src protein
Therapeutic applications
Therapeutic targets
Xenografts
ISSN:0950-9232, 1476-5594, 1476-5594
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Zusammenfassung:Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest malignancies. It is phenotypically heterogeneous with a highly unstable genome and provides few common therapeutic targets. We found that MCL1, Cofilin1 (CFL1) and SRC mRNA were highly expressed by a wide range of these cancers, suggesting that a strategy of dual MCL-1 and SRC inhibition might be efficacious for many patients. Immunohistochemistry revealed that MCL-1 protein was present at high levels in 94.7% of patients in a cohort of PDACs from Australian Pancreatic Genome Initiative (APGI). High MCL1 and Cofilin1 mRNA expression was also strongly predictive of poor outcome in the TCGA dataset and in the APGI cohort. In culture, MCL-1 antagonism reduced the level of the cytoskeletal remodeling protein Cofilin1 and phosphorylated SRC on the active Y416 residue, suggestive of reduced invasive capacity. The MCL-1 antagonist S63845 synergized with the SRC kinase inhibitor dasatinib to reduce cell viability and invasiveness through 3D-organotypic matrices. In preclinical murine models, this combination reduced primary tumor growth and liver metastasis of pancreatic cancer xenografts. These data suggest that MCL-1 antagonism, while reducing cell viability, may have an additional benefit in increasing the antimetastatic efficacy of dasatinib for the treatment of PDAC.
Bibliographie:ObjectType-Article-1
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ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-019-1091-0