Synergy between microtubule destabilizing agents and neurokinin 1 receptor antagonists identified by an siRNA synthetic lethal screen

Abstract

Coordinated microtubule polymerization and depolymerization is essential for numerous biological functions, including mitotic spindle formation, making microtubules a prime target for cancer therapy. Disruption of microtubules with microtubule destabilizing agents (MDAs) induces cell cycle arrest in mitosis and typically leads to the induction of apoptosis. To uncover proteins and signaling pathways involved in MDA cytotoxicity, we developed a short interfering RNA (siRNA) synthetic lethal screen, which identified gene products that sensitized human glioblastoma cells to sub‐lethal concentrations of two MDAs. The neurokinin 1 receptor (NK1R) was selected for further studies due to its expression in various cancer cells, involvement in regulating cell death pathways and the availability of various pharmacological inhibitors. The NK1R antagonist L‐733,060 phenocopied NK1R siRNA and produced a synergistic increase in the cytotoxicity of four different MDAs. This synergistic toxicity was seen in glioblastoma, bladder, cervical and breast cancer cells. Microtubule stabilizing agents (MSAs) and DNA interacting agents failed to induce synergistic toxicity when treated in combination with L‐733,060 suggesting an effect that is specific to MDAs. These results illustrate the potential for synthetic lethal siRNA screens to identify chemosensitivity nodes for MDAs that might be of clinical value.