Ret-driven inflammation is a potential therapeutic target in ER+ breast cancer subtype

SA. VALLONE; A. BOTTOS; M GARCÍA SOLÁ; NE. HYNES; EC. KORDON; A. GATTELLI

Conferencia; Second AACR International Conference Translational Cancer Medicine; 2018

American Association for Cancer Research

Ret is a receptor tyrosine kinase that promotes proliferation, migration and inflammation. Clinically, oncogenic Ret mutations were first identified in human thyroid cancer. Later, Ret fusion proteins were found in lung adenocarcinomas. For these patients, inhibitors that block Ret kinase activity are currently used in clinical studies. In breast cancer Ret mutations are infrequent. However, Ret overexpression occurs in approximately 40% of human breast tumors and high Ret levels correlate with decreased overall survival. Recently, using a new transgenic mouse strain, Ret/MTB, with the MMTV promoter controlling Ret expression in a mammary gland specific and doxycycline-inducible manner, we have shown that none mutated Ret is an oncogenic trigger. The Ret/MTB mammary tumors express Ret, the therapeutic target estrogen receptor (ER) and show no amplification of Her2. Importantly, these tumors are sensitive to Ret inhibitors but are resistant to endocrine therapy, recapitulating features of a selected sub-group of human ER+ breast. Notably, these tumors also exhibit high levels of tumor-associated inflammatory cells, similarly previously observed in thyroid tumors. In this sense, the pro-inflammatory signaling observed might be a mechanism underlying the growth of tumors that remain dependent on the Ret pathway.By RNA-seq analysis we have verified an inflammatory signature present in Ret/MTB-tumors. We have determined that a specific inflammatory population, FACS-identified as neutrophils, is reduced by Ret downregulation, which is accompanied by tumor reduction. This result was confirmed by administration of Ret inhibitor in both Ret/MTB transgenic mouse model and in an allograft Ret+ tamoxifen resistant breast cancer model: using immune-staining we have found a reduction of intratumoral granulocytes in Ret-inhibitor treated mice respect to vehicle treatment. In addition, using cytokine arrays, we have been identified CXCL1 and G-CSF as the candidates to contribute to Ret-driven tumor progression. We are currently developing and testing new strategies of anti-inflammatory therapy in pre-clinical studies.Based on this, Ret overexpression in ER+ breast tumors could be a critical biomarker of hormone-resistance and a crucial predictor for response to alternative targeted therapies, as the use of anti-inflammatory therapy.