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

Lesley Castillo; Adelaide I. J. Young; Amanda Mawson; Pia Schafranek; Angela M. Steinmann; Danielle Nessem; Ashleigh Parkin; Amber L. Johns; Angela Chou; Andrew M. K. Law; Morghan C. Lucas; Kendelle J. Murphy; Niantao Deng; David Gallego-Ortega; Catherine E. Caldon; null Australian Pancreatic Cancer Genome Initiative (APGI); Neil D. Merrett; Paul Timpson; Marina Pajic; Christopher J. Ormandy; Samantha R. Oakes

doi:10.1038/s41388-019-1091-0

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

Lesley Castillo, Adelaide I. J. Young, Amanda Mawson, Pia Schafranek, Angela M. Steinmann, Danielle Nessem, Ashleigh Parkin, Amber L. Johns, Angela Chou, Andrew M. K. Law, Morghan C. Lucas, Kendelle J. Murphy, Niantao Deng, David Gallego-Ortega, Catherine E. Caldon, Australian Pancreatic Cancer Genome Initiative (APGI), Neil D. Merrett, Paul Timpson, Marina Pajic, Christopher J. OrmandySamantha R. Oakes

Western Sydney University

Research output: Contribution to journal › Article › peer-review

19 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1821-1829
Number of pages	9
Journal	Oncogene
Volume	39
Issue number	8
DOIs	https://doi.org/10.1038/s41388-019-1091-0
Publication status	Published - 2020

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Keywords

adenocarcinoma
antineoplastic agent
genomes
pancreatic duct
protein, tyrosine kinase

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41388-019-1091-0

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Castillo, L., Young, A. I. J., Mawson, A., Schafranek, P., Steinmann, A. M., Nessem, D., Parkin, A., Johns, A. L., Chou, A., Law, A. M. K., Lucas, M. C., Murphy, K. J., Deng, N., Gallego-Ortega, D., Caldon, C. E., Australian Pancreatic Cancer Genome Initiative (APGI), Merrett, N. D., Timpson, P., Pajic, M., ... Oakes, S. R. (2020). MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma. Oncogene, 39(8), 1821-1829. https://doi.org/10.1038/s41388-019-1091-0

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title = "MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma",

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.",

keywords = "adenocarcinoma, antineoplastic agent, genomes, pancreatic duct, protein, tyrosine kinase",

author = "Lesley Castillo and Young, {Adelaide I. J.} and Amanda Mawson and Pia Schafranek and Steinmann, {Angela M.} and Danielle Nessem and Ashleigh Parkin and Johns, {Amber L.} and Angela Chou and Law, {Andrew M. K.} and Lucas, {Morghan C.} and Murphy, {Kendelle J.} and Niantao Deng and David Gallego-Ortega and Caldon, {Catherine E.} and {Australian Pancreatic Cancer Genome Initiative (APGI)} and Merrett, {Neil D.} and Paul Timpson and Marina Pajic and Ormandy, {Christopher J.} and Oakes, {Samantha R.}",

year = "2020",

doi = "10.1038/s41388-019-1091-0",

language = "English",

volume = "39",

pages = "1821--1829",

journal = "Oncogene",

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Castillo, L, Young, AIJ, Mawson, A, Schafranek, P, Steinmann, AM, Nessem, D, Parkin, A, Johns, AL, Chou, A, Law, AMK, Lucas, MC, Murphy, KJ, Deng, N, Gallego-Ortega, D, Caldon, CE, Australian Pancreatic Cancer Genome Initiative (APGI), , Merrett, ND, Timpson, P, Pajic, M, Ormandy, CJ & Oakes, SR 2020, 'MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma', Oncogene, vol. 39, no. 8, pp. 1821-1829. https://doi.org/10.1038/s41388-019-1091-0

TY - JOUR

T1 - MCL-1 antagonism enhances the anti-invasive effects of dasatinib in pancreatic adenocarcinoma

AU - Castillo, Lesley

AU - Young, Adelaide I. J.

AU - Mawson, Amanda

AU - Schafranek, Pia

AU - Steinmann, Angela M.

AU - Nessem, Danielle

AU - Parkin, Ashleigh

AU - Johns, Amber L.

AU - Chou, Angela

AU - Law, Andrew M. K.

AU - Lucas, Morghan C.

AU - Murphy, Kendelle J.

AU - Deng, Niantao

AU - Gallego-Ortega, David

AU - Caldon, Catherine E.

AU - Australian Pancreatic Cancer Genome Initiative (APGI), null

AU - Merrett, Neil D.

AU - Timpson, Paul

AU - Pajic, Marina

AU - Ormandy, Christopher J.

AU - Oakes, Samantha R.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - adenocarcinoma

KW - antineoplastic agent

KW - genomes

KW - pancreatic duct

KW - protein, tyrosine kinase

UR - http://hdl.handle.net/1959.7/uws:57858

U2 - 10.1038/s41388-019-1091-0

DO - 10.1038/s41388-019-1091-0

M3 - Article

SN - 0950-9232

VL - 39

SP - 1821

EP - 1829

JO - Oncogene

JF - Oncogene

IS - 8

ER -

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

Abstract

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Keywords

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