Targeting RAS-mutant cancer cells using a synthetic RAS-activated cancer killing system

Despite being the most commonly mutated proteins in cancer, oncogenic RAS proteins remain largely untapped as pharmacological targets. Here, we report a synthetic cancer-killing platform, termed 'RAS-activated cancer killing (RACK)' system. Leveraging a transcriptional sensor designed to detect oncogenic RAS signals with high specificity, RACK achieves targeted identification and elimination of RAS-mutant cancer cells. RACK can potently target a range of RAS and non-RAS mutants, including, but not limited to KRAS, NRAS, BRAF, and RTKs. Notably, RACK can maintain its efficacy against cancer cells that have developed acquired resistance, outperforming conventional inhibitors. In vivo, RACK selectively inhibits RAS-mutant tumor growth in xenograft models, including those intractable by allele-specific inhibitors. Furthermore, the modular design of RACK allows rational optimization of promoter inputs and therapeutic outputs. Collectively, RACK introduces a pioneering drug approach for detecting and treating RAS-mutant cancers, paving the way for overcoming challenges associated with currently undruggable cancer targets.