Inhibitors Targeting Mitosis: Tales of How Great Drugs against a Promising Target Were Brought Down by a Flawed Rationale

Edina Komlodi-Pasztor,Antonio Tito Fojo,Dan L Sackett

doi:10.1158/1078-0432.ccr-11-0999

Abstract

Although they have been advocated with an understandable enthusiasm, mitosis-specific agents such as inhibitors of mitotic kinases and kinesin spindle protein have not been successful clinically. These drugs were developed as agents that would build on the success of microtubule-targeting agents while avoiding the neurotoxicity that encumbers drugs such as taxanes and vinca alkaloids. The rationale for using mitosis-specific agents was based on the thesis that the clinical efficacy of microtubule-targeting agents could be ascribed to the induction of mitotic arrest. However, the latter concept, which has long been accepted as dogma, is likely important only in cell culture and rapidly growing preclinical models, and irrelevant in patient tumors, where interference with intracellular trafficking on microtubules is likely the principal mechanism of action. Here we review the preclinical and clinical data for a diverse group of inhibitors that target mitosis and identify the reasons why these highly specific, myelosuppressive compounds have failed to deliver on their promise.

Highlights

On the premise that tumors harbor a larger fraction of actively dividing cells than do normal tissues and should be more vulnerable to agents aimed at cell division, researchers have developed drugs to target numerous components of this intricate process as chemotherapeutics
We would argue that the neutropenia observed in many of the treated patients represents a biomarker or surrogate that clearly proves the drug hit the target and inhibited mitosis
Mitotic kinase inhibitors were developed as nonneurotoxic alternatives to microtubuletargeting agents (MTA); the rationale behind the development of these agents, i.e., the thesis that MTAs kill cells in human tumors only by inhibiting mitosis, meant that if unrecognized mechanisms proved to be important, such agents would fail when they reached the clinic

Summary

Introduction

On the premise that tumors harbor a (much) larger fraction of actively dividing cells than do normal tissues and should be more vulnerable to agents aimed at cell division, researchers have developed drugs to target numerous components of this intricate process as chemotherapeutics. This makes such tumors indifferent to drugs that target cell proliferation or proteins whose expression is highly restricted to one phase of the cell cycle. This rate of doubling is markedly faster than that found in any solid tumor in humans, and this difference may be significant for target genes/proteins whose expression is highly restricted during the cell cycle, such as occurs with mitosis-specific proteins.

Results

Conclusion