The interaction of CDC6 and Tmod3 accelerates resistance to paclitaxel through focal adhesion assembly

The widespread clinical application of paclitaxel (PTX) in cancer treatment has been significantly limited by the emergence of drug resistance and drug-tolerant persisters. Through genome-wide CRISPR/Cas9 screening, we identified cell division cycle 6 (CDC6) as a critical determinant of cell adhesion-mediated paclitaxel resistance. CDC6, an essential DNA replication licensing factor, functions through a pathway distinct from well-characterized resistance mechanisms. The depletion of CDC6 considerably increases paclitaxel-induced cell death. Beyond its established role in stabilizing chromosomes, our findings indicate that tropomodulin-3 (Tmod3) interacts with CDC6 in the cytoplasm. This interaction enhances CDC6 protein stability and drives drug-resistant phenotypes through regulating actin cytoskeleton remodeling and facilitating focal adhesion assembly. In addition, pharmacological or genetic inhibition of CDC6 notably sensitizes the antitumor efficacy of paclitaxel both in vitro and in vivo. Collectively, our studies elucidate the mechanisms through which CDC6 functions as a key regulator of paclitaxel resistance and provide a potential strategy to enhance paclitaxel efficacy through cytoskeletal-adhesion axis modulation.