Abstract 704: Scaffold protein KSR1 is negatively regulated by merlin and promotes tumor development in merlin deficient tumors

Accumulated evidence suggests that the Ras/Raf/MEK/ERK pathway plays a crucial role in the development of Merlin-deficient tumours. However, the mechanism in which Merlin precisely suppresses this mitogenic signalling pathway has remained poorly understood. In addition, drug specificity, side effects and drug resistance are serious problems when treating patients with MEK inhibitors and therefore a more specific therapeutic target needs to be identified. Using our primary human in vitro model and three complementary approaches including lentiviral shRNA, active mutants and use of a clinically approved inhibitor, we report that Ras/Raf/MEK/ERK scaffold protein Kinase Suppressor of Ras 1 (KSR1) plays a vital role in promoting schwannoma proliferation, multipolar morphology and other pathological phenotypes. Proteomic analysis suggests that merlin shares multiple binding partners with KSR1 incl DCAF1 from the E3 Ubiquitin Ligase CRL4DCAF1, which is directly associated with and functionally inhibited by the tumour suppressor Merlin in the nucleus. Functional study suggests that KSR1 and DCAF1 might co-operate and/or complement to regulate schwannoma9s proliferation. These findings demonstrate that Merlin disrupts Ras/Raf/MEK/ERK activity at the scaffold protein level and also suggest that KSR1 is a specific therapeutic target for Merlin-deficient tumours. Citation Format: Clemens O. Hanemann, Lu Zhou, Sylwia Ammoun, Edwin Lasonder, Vikram Sharma, Juergen Muller, Emanuela Ercolano. Scaffold protein KSR1 is negatively regulated by merlin and promotes tumor development in merlin deficient tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 704. doi:10.1158/1538-7445.AM2015-704