Modeling heterogeneity of Triple-Negative Breast Cancer highlights potency of WEE1 and BCL-XL targeting

Lamballe, F.; Ahmad, F.; Vinik, Y.; Castellanet, O.; Daian, F.; Mueller, A.; Koehler, U.; Bailly, A.-L.; Josselin, E.; Castellano, R.; Cayrou, C.; Charafe-Jauffret, E.; Mills, G. B.; Geli, V.; Borg, J.-P.; Lev, S.; Maina, F.

doi:10.1101/2020.06.22.164418

bioRxiv · 10.1101/2020.06.22.164418

Modeling heterogeneity of Triple-Negative Breast Cancer highlights potency of WEE1 and BCL-XL targeting

Lamballe, F.·Ahmad, F.·Vinik, Y.·Castellanet, O.·Daian, F.·Mueller, A.·Koehler, U.·Bailly, A.-L.·Josselin, E.·Castellano, R.·Cayrou, C.·Charafe-Jauffret, E.·Mills, G. B.·Geli, V.·Borg, J.-P.·Lev, S.·Maina, F.

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Abstract

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.

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Lamballe, F., Ahmad, F., Vinik, Y., Castellanet, O., Daian, F., Mueller, A., Koehler, U., Bailly, A.-L., Josselin, E., Castellano, R., Cayrou, C., Charafe-Jauffret, E., Mills, G. B., Geli, V., Borg, J.-P., Lev, S., Maina, F.. 2020-06-22. Modeling heterogeneity of Triple-Negative Breast Cancer highlights potency of WEE1 and BCL-XL targeting. https://doi.org/10.1101/2020.06.22.164418

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