Paper dels fibroblasts en l'adquisició i el manteniment de la resistència del càncer de mama a les teràpies anti-HER2. Identificació de nous receptors compensatoris de tirosina quinasa.

Patricia Fernández Nogueira

Dr. Pere Gascón Dra. Vanessa Almendro

Els nostres resultats destaquen la contribució essencial de l'estroma en la resistència a la quimioteràpia i la utilitat potencial de centrar-se en les vies FGFR2 i RET, com a nous mecanismes de resistència a les teràpies dirigides a HER2 en el càncer de mama; aquesta estratègia podria superar la resistència dirigint-se tant a clons resistents que sobreexpressen FGFR2/RET per mantenir la supervivència impulsada per HER2 com a fibroblasts genèticament estables responsables d'induir i mantenir el fenotip resistent. A continuació, proposem que la inhibició de les vies FGFR2 i RET podria convertir-se en una estratègia de rescat prometedora després del fracàs de Trastuzumab i Lapatinib en pacients amb càncer de mama HER2 positiu. A més, l'addició de teràpies anti-FGFR i RET en les primeres etapes del tractament del càncer de mama pot prevenir el desenvolupament de resistències.

As a summary, the specific main potential sanitary interventions derived from this thesis will include:  The implementation of the analysis of FGFR2 and RET expression in HER2+ primary breast cancer samples as a biomarker of response to HER2-targeted therapies. This will allow a more accurate identification of those patients who will benefit or not from the currently available HER2-targeted therapies, avoiding the application of un-useful cytotoxic therapies to the patients.  The design of a clinical trial to test the use of FGFR2 and RET inhibitors as second line (after Trastuzuamb therapy based relapse) or third line (after Lapatinib therapy based relapse), or even as first line in combination with Trastuzumab, to define a new rationale for HER2+ breast cancer patients treatment, that will imply a great improvement for the treatment of those patients that nowadays do not have an alternative treatment after recurrence.  The design of new therapies that target the TAF population in HER2 tumours, which will prevent the development of acquired fibroblast mediated resistance and would increase the efficacy of trastuzumab and lapatinib based treatments. Therefore, with this thesis, we have identified a novel and clinically relevant approach for HER2 breast cancer therapy that can be exploited to improve the therapeutic options for patients with HER2 positive breast cancer and delay the onset of resistance, as well as improve the identification of those patients that will initially respond to current therapies. We have also showed that the novel resistance mechanism here defined can be overcome by using two commercial inhibitors that are currently being used in clinical trials for other oncological applications, which will facilitate and mark down the transference of these findings into the clinics in our sanitary system.

Stroma; Chemotherapy Resistance; FGFR2 Pathway; RET Pathway; New Mechanisms of Resistance; HER2-targeted Therapies; Breast Cancer; Resistant Clones; HER2-driven Survival; Genetically Stable Fibroblasts; Resistant Phenotype; Inhibition; Promising Salvage Strategy; Trastuzumab Failure; Lapatinib Failure; HER2-positive Breast Cancer; Anti-FGFR Therapies; Anti-RET Therapies; Early Stages of Breast Cancer Treatment; Resistance Development