Fibroblast role in the acquisition and maintenance of breast càncer resistance to anti-her2 therapies. Identification of novel compensatory tyrosine kinase receptors

Patricia Fernández Nogueira

Dr. Pere Gascón Dra. Vanessa Almendro

Our results highlight the essential contribution of the stroma in resistance to chemotherapy and the potential utility of focusing on the FGFR2 and RET pathways, as new mechanisms of resistance to HER2 –targeted therapies in breast cancer; this strategy might overcome resistance by targeting both resistant clones that overexpress FGFR2/RET to maintain HER2-driven survival and genetically stable fibroblasts responsible for inducing and maintaining the resistant phenotype. We then propose that inhibition of FGFR2 and RET pathways might become a promising salvage strategy after Trastuzumab and Lapatinib failure in patients with HER2‐ positive breast cancer. Moreover, the addition of anti‐FGFR and RET therapies in the early stages of breast cancer treatment may prevent resistance development.

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