Abstract
We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.
| Original language | English (US) |
|---|---|
| Article number | e1600957 |
| Journal | Science advances |
| Volume | 3 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 1 2017 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
Cite this
A murine preclinical syngeneic transplantation model for breast cancer precision medicine. / Federico, Lorenzo; Chong, Zechen; Zhang, Dong; McGrail, Daniel J.; Zhao, Wei; Jeong, Kang Jin; Vellano, Christopher P.; Ju, Zhenlin; Gagea, Mihai; Liu, Shuying; Mitra, Shreya; Dennison, Jennifer B.; Lorenzi, Philip L.; Cardnell, Robert; Diao, Lixia; Wang, Jing; Lu, Yiling; Byers, Lauren A.; Perou, Charles M.; Lin, Shiaw Yih; Mills, Gordon.
In: Science advances, Vol. 3, No. 4, e1600957, 01.04.2017.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - A murine preclinical syngeneic transplantation model for breast cancer precision medicine
AU - Federico, Lorenzo
AU - Chong, Zechen
AU - Zhang, Dong
AU - McGrail, Daniel J.
AU - Zhao, Wei
AU - Jeong, Kang Jin
AU - Vellano, Christopher P.
AU - Ju, Zhenlin
AU - Gagea, Mihai
AU - Liu, Shuying
AU - Mitra, Shreya
AU - Dennison, Jennifer B.
AU - Lorenzi, Philip L.
AU - Cardnell, Robert
AU - Diao, Lixia
AU - Wang, Jing
AU - Lu, Yiling
AU - Byers, Lauren A.
AU - Perou, Charles M.
AU - Lin, Shiaw Yih
AU - Mills, Gordon
PY - 2017/4/1
Y1 - 2017/4/1
N2 - We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.
AB - We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments.
UR - http://www.scopus.com/inward/record.url?scp=85042035716&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85042035716&partnerID=8YFLogxK
U2 - 10.1126/sciadv.1600957
DO - 10.1126/sciadv.1600957
M3 - Article
C2 - 28439535
AN - SCOPUS:85042035716
VL - 3
JO - Science advances
JF - Science advances
SN - 2375-2548
IS - 4
M1 - e1600957
ER -