Microtubule Inhibitors

Abstract

Overview Central to the ever‐growing list of anticancer therapies is the microtubule inhibitors (MTIs), a class of naturally derived compounds that bind tubulin or microtubules and disrupt the function of the cell's cytoskeleton. The vinca alkaloids were among the first drugs to receive FDA approval for the treatment of cancer, even before the α/β‐tubulin dimer was identified as their target. Today, 60 years from their entry to the clinic, these microtubule‐destabilizing drugs continue to be central in current and widely used chemotherapy regimens. Paclitaxel was the first natural product identified to bind microtubule polymers instead of soluble tubulin dimers, and the prototype of the new class of microtubule‐stabilizing drugs. Together, both destabilizing and stabilizing drugs form the family of MTIs, which continues to expand with the clinical approval of several other plant‐, marine sponge‐ and bacteria‐derived compounds, such as epothilones, halicondrin B, maytansinoids, and auristatins. Even in the current era of targeted therapies and immune checkpoint inhibitors, MTIs are among the most effective drugs for the treatment of solid tumors and hematologic malignancies. For decades, these drugs were thought to exert their antitumor activity solely by inhibiting cancer cell division. Current evidence demonstrates that MTIs can effectively kill not only dividing but also nondividing interphase cells, which represent the most abundant cell population in patient tumors. In this chapter, we will discuss MTI mechanism of action or “inaction,” all the way from molecular interactions to cancer cell effects to patient treatment. Fundamental to this chapter is the thesis that MTIs are “targeted therapies,” which is a big departure from the established view that these drugs are nonspecific, generally cytotoxic chemotherapy drugs. Once accepted, this thesis provides previously unrecognized opportunities for precision oncology, taking advantage of the distinct functions and alterations of the MT cytoskeleton in different tumor types and individual patients.