Oncogenic signaling networks and interaction of tumors with the microenvironment

Prof. Dr. Robert Zeiser (Hematology and Oncology, University Medical Center Freiburg)

Patients with BRAFV600E/K-driven melanoma respond to BRAF inhibition due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In cells with mutations that activate RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We could recently demonstrate that paradoxical ERK activation can drive chronic lymphocytic leukemia in the absence of RAS mutations via enhancing signals derived from the BCR-proximal spleen tyrosine kinase (SYK) (Yaktapour N et al. J Clin Invest 124, 5074-5084, 2014). Increased ERK activation can be antagonized by MEK inhibition which is now also applied clinically as BRAF/MEK inhibitor combination for patients with metastatic melanoma. Recently it was shown that STAT1/IFN activity is closely linked to the response to MEK inhibition in melanoma (Cancer Discov. 2015;5: 343). Our preliminary data indicate that signaling in melanoma cells is regulated by different microRNAs (miRs). We plan to use the established tools to study the impact of different miRs on signaling in T cells residing in the melanoma microenvironment in mice carrying a Braf^V600E mutation and Pten loss which leads to melanoma development.