Dysregulation Of Myristoylated Alanine-Rich C Kinase Substrate (Marcks): A Novel Therapeutic Target In Renal Cell Carcinoma

Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/VEGF signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably VEGF-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multi-kinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multi-kinase inhibitors. Citation Format: Ching-Hsien Chen, Wen-Hsin Chang, Eric Yu, Muhammad S. Arif, Reen Wu, Robert H. Weiss. Dysregulation of myristoylated alanine-rich C kinase substrate (MARCKS): A novel therapeutic target in renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1810. doi:10.1158/1538-7445.AM2017-1810