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

M. GARCÍA SOLÁ; A. GATTELLI; S. VALLONE; N.E. HYNES; A. BOTTOS; EC.KORDON

Conferencia; Second AACR International Conference Translational Cancer Medicine; 2018

AACR

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 non-mutated Ret is an oncogenic trigger. The Ret/MTB mammary tumors express Ret and the estrogen receptor (ER), while they show no amplification of Her2. Importantly, these tumors are sensitive to Ret inhibitors, but resistant to endocrine therapy and exhibit high levels of tumor-associated inflammatory cells, as previously observed in Ret-driven thyroid tumors. These observations suggest that pro-inflammatory signaling might be relevant for Ret-dependent tumor growth. By RNA-seq analysis we have identified an inflammatory signature present in Ret/MTB-tumors. Besides, in these neoplasias, Ret downregulation caused tumor size and a significant decrease of FACS-identified neutrophils. Similarly, administration of a selective Ret kinase inhibitor to Ret/MTB tumor-bearing transgenic mice and to wild type mice carrying Ret+ tamoxifen-resistant mammary tumor allografts induced reduction of intratumoral granulocytes. In addition, using cytokine arrays, we have identified CXCL1 and G-CSF as possible candidates to contribute to Ret-driven tumor progression. We are currently developing and testing new strategies of anti-inflammatory therapies in pre-clinical studies.Based on these results, Ret overexpression in ER+ breast tumors might be a relevant biomarker of hormone-resistance and a predictor for response to alternative targeted therapies, as the use of anti-inflammatory drugs.