78 : Therapeutic inhibition of Gp130/Jak/Stat3-dependent cytokine signaling suppresses WNT-dependent colon cancer formation

Abstract

The initiating mutations in the majority of sporadic and familial colorectal cancers (CRC) occur in the tumor suppressor gene APC and result in nuclear accumulation of β -catenin associated with aberrant activation of the WNT pathway. Meanwhile, a tightly controlled burst of WNT signalling is required for regeneration of the intestinal epithelium after injury and ensures homeostasis. Since identification of therapeutic WNT pathway inhibitors remains challenging, we explored whether genetic interference with cytokine-dependent gp130/Jak/Stat3 signaling affects the intestine’s response to oncogenic WNT signaling. In situations of chronic inflammation and excessive secretion of interleukin- (IL) 6-family cytokines, we have previously shown that gp130 engagement simultaneously activates Stat3 and the mTOR complex 1, and that the mTorc1-specific inhibitor RAD001 potently suppressed initiation and progression of colitis-associated CRC (Thiem et al., J Clin Invest (2013) 123:767). Here we describe that partial genetic suppression of either Stat3 expression, or of its gp130 receptor-dependent activation, prevents tumorigenesis in mouse models of sporadic and of inherited CRC. Likewise, therapeutic administration of the Jak-kinase inhibitors effectively blocked de novo tumor initiation and progression in these models. Surprisingly, gp130/Jak/Stat3 pathway inhibition selectively impaired the growth of mutant APC mouse tumors and human CRC cell xenografts without affecting homeostasis of the non-neoplastic intestinal epithelium. We identify Stat3-dependent Bmi1 induction and the resulting repression of p16 and p21 as the mechanism by which the gp130/Jak/Stat3 pathway modulates the cellular response to aberrant WNT signaling. Meanwhile, a large proportion human CRC harbours coinciding WNT- and STAT3 gene activation signatures. Interference with the gp130/Jak/Stat3 pathway is therefore readily exploitable for the therapeutic treatment of CRC.