TY - JOUR
T1 - Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance
AU - Lamballe, Fabienne
AU - Ahmad, Fahmida
AU - Vinik, Yaron
AU - Castellanet, Olivier
AU - Daian, Fabrice
AU - Müller, Anna Katharina
AU - Köhler, Ulrike A.
AU - Bailly, Anne Laure
AU - Josselin, Emmanuelle
AU - Castellano, Rémy
AU - Cayrou, Christelle
AU - Charafe-Jauffret, Emmanuelle
AU - Mills, Gordon B.
AU - Géli, Vincent
AU - Borg, Jean Paul
AU - Lev, Sima
AU - Maina, Flavio
N1 - Publisher Copyright:
© 2020 The Authors. Advanced Science published by Wiley-VCH GmbH
PY - 2021/2/3
Y1 - 2021/2/3
N2 - Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV-R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor is generated. MMTV-R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL-XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.
AB - Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV-R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor is generated. MMTV-R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV-R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL-XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL-XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.
KW - BCL-XL
KW - MET
KW - WEE1
KW - cancer mouse model
KW - drug resistance
KW - signaling reprogramming
KW - triple-negative breast cancer
UR - http://www.scopus.com/inward/record.url?scp=85097633855&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85097633855&partnerID=8YFLogxK
U2 - 10.1002/advs.202003049
DO - 10.1002/advs.202003049
M3 - Article
AN - SCOPUS:85097633855
SN - 2198-3844
VL - 8
JO - Advanced Science
JF - Advanced Science
IS - 3
M1 - 2003049
ER -