Small molecule inhibition of speckle-type POZ protein-substrate interactions for the treatment of renal cell carcinoma

Abstract

Renal cell carcinoma (RCC) is the most common type of kidney cancer and is highly resistant to therapy, clear cell (cc)RCC accounts for 70–75% of cases. Current treatment options include high-dose interleukin-2 (IL-2), and inhibitors of mTOR and HIF-1 downstream signaling. Recently, speckle-type POZ protein (SPOP) has emerged as a promising therapeutic candidate for ccRCC treatment. SPOP is a subunit of the cullin-RING ligase (CRL)-type E3 ligase complex that plays important roles in regulating cell death and proliferation. In 99% of ccRCC tumors, SPOP is overexpressed and mislocalized to the cytoplasm where it acts to lower levels of tumour suppressor genes such as PTEN and DUSP7 by targeting them for ubiquitin-mediated proteasomal degradation. Guo et al . have reported the identification of small-molecule inhibitors that block SPOP-substrate interactions, preventing SPOP-mediated ubiquitination and degradation of PTEN and DUSP7, and suppressing the growth of ccRCC cancer cells in vitro and tumor growth in vivo . These data suggest that therapeutic targeting of SPOP may provide new opportunities for the treatment of patients with ccRCC.