by Keyword: her2

Rivas, Elisa I., Linares, Jenniffer, Zwick, Melissa, Gómez-Llonin, Andrea, Guiu, Marc, Labernadie, Anna, Badia-Ramentol, Jordi, Lladó, Anna, Bardia, Lídia, Pérez-Núñez, Iván, Martínez-Ciarpaglini, Carolina, Tarazona, Noelia, Sallent-Aragay, Anna, Garrido, Marta, Celià-Terrassa, Toni, Burgués, Octavio, Gomis, Roger R., Albanell, Joan, Calon, Alexandre, (2022). Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors Nature Communications 13, 5310

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients’ response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.

JTD Keywords: activation, cells, efficacy, enrichment analysis, expression, infiltrating lymphocytes, survival, therapy, trastuzumab, Her2-positive breast-cancer

Alcon C, Gómez Tejeda Zañudo J, Albert R, Wagle N, Scaltriti M, Letai A, Samitier J, Montero J, (2021). ER+ Breast Cancer Strongly Depends on MCL-1 and BCL-xL Anti-Apoptotic Proteins Cells 10,

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.

JTD Keywords: apoptosis, bh3 mimetics, cell-line, chemotherapy, classification, dbp, death, er+ breast cancer, fulvestrant, her2, inhibitor, kinase, pik3ca, priming, resistance, targeted therapies, Apoptosis, Bh3 mimetics, Dbp, Endocrine therapy, Er plus breast cancer, Er+ breast cancer, Priming, Resistance, Targeted therapies