Abstract 5162: Development of a dual inhibitor of pan-RAF and angiogenesis for the treatment of metastatic colorectal cancer with mutant K-RAS

Abstract

Abstract Colorectal cancer(CRC) is one of the most common cancers and a leading cause of cancer-related death in the western world. K-RAS mutation has been reported in 40% of colorectal cancer patients. KRAS mutations have been significantly associated with lack of response to treatment with the anti-EGFR or anti-BRAF. The FDA approved Bevacizumab as the anti-angiogenic agent for the treatment standard of care in metastatic CRC. However, K-RAS status does not show benefit from the incorporation of bevacizumab to the first-line IFL chemotherapy. Bevacizumab provides modest or no benefit and almost inevitably causes therapeutic resistance. Therefore, there is a need for the development of new therapeutic approaches for the treatment of colorectal cancers with K-RAS mutation. Because aberrant activation of the RAF- MAPK pathway is frequently found in K-RAS mutant cancer, the B-RAF specific inhibitors have been tested. However, B-RAF specific inhibitor activates C-RAF in RAS mutant cells by inducing RAF dimer formation and paradoxical activation of C-RAF. These observations require the development of pan-RAF inhibitors without inducing paradoxical activation. In addition, acquired resistance to anti-VEGF therapy needs another therapeutic target, such as angiopoietin-TIE2 system. Because the pathway is induced after exposure to anti-VEGF/VEGFR drugs. Therefore, we tried to find dual inhibitors of pan-RAF and angiogenesis using structure based molecular modeling and identified a selective inhibitor, SJ-C1044, which binds to the DFG-out inactive conformation of B-RAF. SJ-C1044 potentially inhibited B-RAF, C-RAF, B-RAF V600E, VEGFR2 and Tie2. SJ-C1044 completely inhibited the phosphorylation of MEK-ERK without paradoxical activation in K-RAS mutant cells. We examined the effects of SJ-C1044 on cell proliferation of colorectal cancer cells with K-RAS or B-RAF mutation. SJ-C1044 displayed potent anti-proliferative activities not only in K-RAS mutant colorectal cancer cells but also in B-RAF mutant colorectal cancer cells. We tested SJ-C1044 in colorectal cancer xenografts with mutant K-RAS and observed 97% reduction of tumor volume. In this study, we discovered an orally active dual inhibitor of pan-RAF and angiogenesis. SJ-C1044 has been shown to suppress mutant K-RAS colorectal cancer cells without activating the MAPK pathway. Our findings suggest that SJ-C1044 could be an excellent preclinical candidate for the treatment of colorectal cancer with mutant K-RAS. Citation Format: Sungpyo Hong, Younghoon Choi, Ho-Seok Kwon, Yong Bin Park, Min-Hyo Ki, Hee Jong Shin, Michael Lee, Soon Kil Ahn. Development of a dual inhibitor of pan-RAF and angiogenesis for the treatment of metastatic colorectal cancer with mutant K-RAS [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 5162. doi:10.1158/1538-7445.AM2017-5162