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

Castillo, L; Young, AIJ; Mawson, A; Schafranek, P; Steinmann, AM; Nessem, D; Parkin, A; Johns, A; Chou, A; Law, AMK; Lucas, MC; Murphy, KJ; Deng, N; Gallego-Ortega, D; Caldon, CE; Australian Pancreatic Cancer Genome Initiative (APGI); Timpson, P; Pajic, M; Ormandy, CJ; Oakes, SR

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

Castillo, L Young, AIJ Mawson, A Schafranek, P Steinmann, AM Nessem, D Parkin, A Johns, A Chou, A Law, AMK Lucas, MC Murphy, KJ Deng, N Gallego-Ortega, D Caldon, CE Australian Pancreatic Cancer Genome Initiative (APGI) Timpson, P Pajic, M Ormandy, CJ Oakes, SR

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Publisher:: Springer Nature [academic journals on nature.com]
Publication Type:: Journal Article
Citation:: Oncogene, 2020, 39, (8), pp. 1821-1829
Issue Date:: 2020-02

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Field	Value	Language
dc.contributor.author	Castillo, L
dc.contributor.author	Young, AIJ
dc.contributor.author	Mawson, A
dc.contributor.author	Schafranek, P
dc.contributor.author	Steinmann, AM
dc.contributor.author	Nessem, D
dc.contributor.author	Parkin, A
dc.contributor.author	Johns, A
dc.contributor.author	Chou, A
dc.contributor.author	Law, AMK
dc.contributor.author	Lucas, MC
dc.contributor.author	Murphy, KJ
dc.contributor.author	Deng, N
dc.contributor.author	Gallego-Ortega, D
dc.contributor.author	Caldon, CE
dc.contributor.author	Australian Pancreatic Cancer Genome Initiative (APGI)
dc.contributor.author	Timpson, P
dc.contributor.author	Pajic, M
dc.contributor.author	Ormandy, CJ
dc.contributor.author	Oakes, SR
dc.date.accessioned	2020-12-18T01:54:41Z
dc.date.available	2019-10-28
dc.date.available	2020-12-18T01:54:41Z
dc.date.issued	2020-02
dc.identifier.citation	Oncogene, 2020, 39, (8), pp. 1821-1829
dc.identifier.issn	0950-9232
dc.identifier.issn	1476-5594
dc.identifier.uri	http://hdl.handle.net/10453/144833
dc.description.abstract	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.
dc.format	Print-Electronic
dc.language	eng
dc.publisher	Springer Nature [academic journals on nature.com]
dc.relation.ispartof	Oncogene
dc.relation.isbasedon	10.1038/s41388-019-1091-0
dc.rights	info:eu-repo/semantics/openAccess
dc.rights	This is a post-peer-review, pre-copyedit version of an article published in Oncogene. The final authenticated version is available online at: https://dx.doi.org/10.1038/s41388-019-1091-0.	en_US
dc.subject	1103 Clinical Sciences, 1112 Oncology and Carcinogenesis
dc.subject.classification	Oncology & Carcinogenesis
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Adenocarcinoma
dc.subject.mesh	Pancreatic Neoplasms
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Drug Synergism
dc.subject.mesh	Myeloid Cell Leukemia Sequence 1 Protein
dc.subject.mesh	Dasatinib
dc.subject.mesh	Adenocarcinoma
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Dasatinib
dc.subject.mesh	Drug Synergism
dc.subject.mesh	Humans
dc.subject.mesh	Myeloid Cell Leukemia Sequence 1 Protein
dc.subject.mesh	Neoplasm Invasiveness
dc.subject.mesh	Pancreatic Neoplasms
dc.title	MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma.
dc.type	Journal Article
utslib.citation.volume	39
utslib.location.activity	England
utslib.for	1103 Clinical Sciences
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Mathematical and Physical Sciences
pubs.organisational-group	/University of Technology Sydney
utslib.copyright.status	open_access	*
pubs.consider-herdc	true
dc.date.updated	2020-12-18T01:54:21Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	39
utslib.citation.issue	8

Abstract:

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.

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http://hdl.handle.net/10453/144833