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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Published in:	Oncogene Vol. 39; no. 8; pp. 1821 - 1829
Main Authors:	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
Language:	English
Published:	London Nature Publishing Group UK 01-02-2020 Nature Publishing Group
Subjects:	13/1 13/106 13/51 14 14/5 42 45 45/61 59 59/5 631/67/1059/602 631/67/1504/1713 631/80/82/23 64 64/60 82 Adenocarcinoma Adenocarcinoma - pathology Animal models Apoptosis Brief Communication Care and treatment Cell Biology Cell culture Cell Line, Tumor Cell viability Cytoskeleton Dasatinib Dasatinib - pharmacology Development and progression Drug Synergism Enzyme inhibitors Gene expression Genetic aspects Genomes Health aspects Human Genetics Humans Immunohistochemistry Internal Medicine Invasiveness Liver cancer Mcl-1 protein Medicine Medicine & Public Health Messenger RNA Metastases Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors Neoplasm Invasiveness Oncology Pancreatic cancer Pancreatic Neoplasms - pathology Patient outcomes Src protein Therapeutic applications Therapeutic targets Xenografts Australia
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Summary:	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.
ISSN:	0950-9232 1476-5594
DOI:	10.1038/s41388-019-1091-0