TY - JOUR T1 - Modeling Heterogeneity of Triple-Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance JF - bioRxiv DO - 10.1101/2020.06.22.164418 SP - 2020.06.22.164418 AU - Fabienne Lamballe AU - Fahmida Ahmad AU - Yaron Vinik AU - Olivier Castellanet AU - Fabrice Daian AU - Anna-Katharina Müller AU - Ulrike A. Köhler AU - Anne-Laure Bailly AU - Emmanuelle Josselin AU - Rémy Castellano AU - Christelle Cayrou AU - Emmanuelle Charafe-Jauffret AU - Gordon B. Mills AU - Vincent Géli AU - Jean-Paul Borg AU - Sima Lev AU - Flavio Maina Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/08/10/2020.06.22.164418.abstract 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, we generated a unique mouse model (MMTV-R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild-type MET receptor. 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 showed that the model faithfully recapitulates inter-tumoral heterogeneity of human TNBC. Further signaling network analysis highlighted potential druggable targets, of which co-targeting of WEE1 and BCL-XL synergistically killed TNBC cells and efficiently induced 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. Our study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.Competing Interest StatementThe authors have declared no competing interest. ER -