Role for Girdin and Daple in melanoma progression and therapy resistance
Birgit Schittek

Melanoma progression is characterized by the acquisition of multiple sequential driver mutations leading to the activation of key oncogenic signaling pathways including MAPK, PI3K/ AKT and G protein signaling. Targeted therapies with MAPK inhibitors result in an initial good response in the majority of melanoma patients; however, most patients rapidly develop therapy resistance. Acquired resistance is mainly achieved by overexpression of RTKs as well as by activation of PI3K/ AKT and Wnt/ β-catenin signaling and reactivation of MAPK signaling. Girdin and Daple are guanine nucleotide exchange modulators that transmit signals from diverse receptors including RTKs and can modulate MAPK, PI3K/ AKT and Wnt/ β-catenin signaling pathways. Overexpression of Girdin and Daple has a negative prognostic impact in patients with melanoma and colorectal cancer; however, the underlying mechanisms including detailed expression pattern and mode of action in tumor progression and in therapy resistance are unknown.​

 

We aim (1) to characterize the expression pattern and the posttranscriptional and posttranslational modifications of Girdin and Daple isoforms during melanoma progression and therapy resistance, (2) to analyze the crosstalk of Girdin and Daple expression with other signaling pathways and the influence on melanoma progression and therapy resistance in vitro, (3) to clarify the role of Girdin and Daple in DNA damage sensing and repair processes, and (4) to evaluate the in vivo relevance of Girdin and Daple in melanoma progression and therapy resistance in suitable mouse models in vivo and in patient material.