A major limitation of clinically used cancer drugs is the lack of specificity resulting in toxicity. To address this, we performed a phenotypically-driven screen to identify optimal multidrug combinations acting with high efficacy and selectivity in clear cell renal cell carcinoma (ccRCC). The search was performed using the Therapeutically Guided Multidrug Optimization (TGMO) method in ccRCC cells (786-O) and nonmalignant renal cells and identified a synergistic low-dose four-drug combination (C2) with high efficacy and negligible toxicity. We discovered that C2 inhibits multipolar spindle pole clustering, a survival mechanism employed by cancer cells with spindle abnormalities. This phenotype was also observed in 786-O cells resistant to sunitinib, the first line ccRCC treatment, as well as in melanoma cells with distinct percentages of supernumerary centrosomes. We conclude that C2-treatment shows a high efficacy in cells prone to form multipolar spindles. Our data suggest a highly effective and selective C2 treatment strategy for malignant and drug-resistant cancers. View Full-Text