A Sticky Situation: How Cellular Adhesion Undermines Chemotherapy

Paclitaxel has long served as a cornerstone of cancer treatment, yet its efficacy is frequently curtailed by the emergence of drug-tolerant 'persister' cells. In a bid to unmask the architects of this resistance, researchers employed a genome-wide CRISPR/Cas9 screen, pinpointing a protein known as cell division cycle 6 (CDC6) as a critical offender. While CDC6 is traditionally recognised for its role in licensing DNA replication within the nucleus, this study reveals it moonlighting in the cytoplasm with a rather troublesome partner.

The investigation demonstrates that CDC6 physically interacts with tropomodulin-3 (Tmod3). This alliance is far from benign; it enhances the stability of the CDC6 protein and orchestrates the remodelling of the actin cytoskeleton. Essentially, this interaction fortifies the cell’s internal scaffolding and promotes focal adhesion assembly, allowing the cancer cell to anchor itself more securely against the chemotherapeutic assault.

Crucially, the study highlights that genetic depletion of CDC6 strips the cells of this defence, rendering them significantly more susceptible to paclitaxel-induced death. Furthermore, the data suggests a promising clinical pivot: combining paclitaxel with inhibitors that target actin filaments yields a synergistic effect, enhancing anti-tumour efficacy both in the petri dish and in vivo. By severing the cytoskeletal-adhesion axis, we may finally be able to outmanoeuvre these resilient cells.