Drug Repurposing Screen on Patient-Derived Organoids Identifies New Therapeutic Drug Combination Against KRAS Mutant Colon Cancer

Patient-derived organoids (PDO) are widely heralded as a drug-screening platform to develop new anti-cancer therapies. Here we use a drug-repurposing library to screen PDOs of colorectal cancer (CRC) to identify drugs that enhance the efficacy of combinatorial targeting of EGFR and MEK in KRAS mutant CRCs. Although this combination achieves significant inhibition of downstream signaling of mutant KRAS, preclinical models revealed its failure to induce robust cell killing. We developed a microscopy-based screen to score drug-induced cytotoxicity in PDOs and tested 414 putative anti-cancer drugs in combination with EGFR/MEK inhibition. A majority of validated hits were microtubule targeting agents that are commonly used in clinical oncology, like taxanes and vinca-alkaloids. One of these drugs, vinorelbine, was consistently effective across a panel of >20 different CRC PDOs. Unlike vinorelbine alone, its combination with EGFR/MEK inhibition induces apoptosis at all stages of the cell cycle, presumably by disrupting the balance between pro- and anti-apoptotic effectors. In mice, the triple combination showed tolerability and superior antitumor activity at clinically relevant doses and scheduling, setting the basis for a clinical trial to treat patients with metastatic RAS mutant CRC.