Ideally, anti-cancer agents target components that are essential for tumor, but not normal, cell proliferation and survival. The success of agents that disrupt mitosis, including Paclitaxel (Taxol®), in prolonging the lives of cancer patients demonstrates that tumors have an enhanced sensitivity to mitotic perturbation.
However, because these compounds inhibit microtubule dynamics in both tumor and normal cells, they display a narrow therapeutic window leading to significant toxicity, incomplete responses, and ultimately, acquired resistance. Given the promise, yet limitation, of current therapies, it is necessary to identify mechanisms that are uniquely required for tumor-cell mitosis, so that we can enhance the repertoire of potential therapeutic entry points.
To identify the compendium of gene products required for tumor cell mitosis, our Lab employs a genome-wide siRNA paclitaxel sensitizer screening approach in non-small cell lung cancer cells. This approach has uncovered an unexpected cohort of gene products that have no previously known functional contribution to mitosis.
Thus, we employ an array of cell biological, biochemical, and proteomic approaches to annotate the contribution of these gene products to mitosis and sensitivity to first-line chemotherapeutics.