Therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models

Abstract

Introduction: KRAS is mutated in ∼80% of pancreatic ductal adenocarcinoma (PDAC), ∼35% of colorectal cancer (CRC) and ∼20% of non-small-cell lung cancer (NSCLC). KRAS remains an intractable drug target and targeting the downstream pathway component is ineffective because feedback mechanisms or parallel pathways provide alternative routes to cell proliferation and/or survival. Results and Discussion: Here we show that CCT3833, the clinical candidate from our in house panRAF/SRC inhibitor series, is active in KRASmutant PDAC, CRC and NSCLC. We demonstrate that CCT3833 inhibits tumor growth in several KRAS-driven cancers via inhibition of RAF and SRC, eliciting therapeutic efficacy at well-tolerated doses in mouse models of human cancer. Conclusion: CCT3833 has entered clinical trials (NCT02437227) for BRAF mutant and BRAF inhibitor-resistant melanomas and our data here show that it is also effective in KRAS mutant cancers, potentially providing a new therapeutic option for these patients.