Abstract 4486: INK128, a novel TORC1/2 inhibitor with potent oral antitumor activity in preclinical models of renal cancer

Abstract

Abstract Objective: Preclinical characterization and evaluation of INK128 alone and in combination with anti-angiogenic agents in models of renal cell carcinoma. Background: mTOR kinase comprises two distinct multi-protein complexes, TORC1 and TORC2, which together regulate processes critical for cell growth and survival. TORC1 regulates protein translation of cell cycle regulators, angiogenic factors, and factors that control cell motility. TORC2 regulates pathways involved in cell metabolism, survival and motility. Through rational drug design we have identified INK128, a potent and selective small molecule, active-site kinase inhibitor of mTOR with excellent drug-like properties. Activity seen with temsirolimus and everolimus, pharmaceutical derivatives of rapamycin and allosteric partial inhibitors of TORC1, provide clinical proof-of-concept for targeting mTOR for cancer therapy. TORC1 is upstream of HIF1/2 and TORC1 and TORC2 are downstream of the VEGF pathways implicated in the tumorigenesis of metastatic renal cell carcinoma (RCC). We have investigated INK128 in preclinical in vitro and in vivo models of renal cell carcinoma (RCC) and compared its activity to other standard of care agents commonly used to treat this disease. Results: INK128 selectively inhibited phosphorylation of S6 and 4EBP1, downstream substrates of TORC1, as well as phosphorylation of AKT downstream of TORC2 in vitro and in vivo. INK128 demonstrated very potent inhibition of tumor cell proliferation and induction of G1 cell cycle arrest in vitro. In mouse tumor models, INK128, rapamycin, avastin and sorafenib displayed anti-tumor efficacy; however, they differ in the mechanisms underlying the anti-tumor activity. INK128 inhibits phosphorylation of AKT, PRAS40, NDRG1, S6 and 4EBP1; rapamycin only inhibits S6 phosphorylation and induces phosphorylation of AKT; sorafenib activates several pathway components that are downstream of TORC1/2. INK128 and rapamycin suppressed tumor growth by directly inhibiting tumor cell proliferation; however neither had much impact on tumor-associated angiogenesis. In contrast, sorafenib and avastin suppressed tumor growth by potently inhibiting tumor angiogenesis. The activity of the combination of INK128 with sorafenib or avastin yielded sustained tumor regression by targeting tumor cells and the microenvironment. Conclusion: INK128 offers a novel approach for the treatment of renal cell carcinoma by targeting TORC1/2 signaling. Additionally, the mechanism of action of INK128 is different than current therapies and may not display cross resistance with current standard of care agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4486. doi:10.1158/1538-7445.AM2011-4486