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
- Publisher:
- Springer Nature [academic journals on nature.com]
- Publication Type:
- Journal Article
- Citation:
- Oncogene, 2020, 39, (8), pp. 1821-1829
- Issue Date:
- 2020-02
Open Access
Copyright Clearance Process
- Recently Added
- In Progress
- Open Access
This item is open access.
Full metadata record
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.
Please use this identifier to cite or link to this item:
Download statistics for the last 12 months
Not enough data to produce graph