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

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 mitosisspecific 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.

Microtubule-targeting agents augment the toxicity of DNA-damaging agents by disrupting intracellular trafficking of DNA repair proteins

“…However, most human tumors have doubling times of 30-60 d or longer (3,5), making it difficult-indeed almost impossible-to explain how mitotic arrest could be the mechanism of action when MTAs are administered to patients. We have proposed that rather than mitotic arrest, the principal mechanism of action of MTAs in a clinical setting is interference with intracellular trafficking during interphase (3,4). Key to this concept is identification of the critical proteins whose impaired trafficking on MTs leads to cytotoxicity.…”

“…Although this explanation applies to rapidly dividing cells in preclinical models, it cannot explain the activity of these agents in tumors in humans because these cells divide much more slowly. For the latter situtation, a different paradigm must explain the activity of MTAs, and we have proposed that interfering with microtubule (MT) trafficking in interphase cells is the principal mechanism of MTA action (3)(4)(5). In breast, ovarian, lung, and head and neck cancers, as well as in most lymphomas, combination regimens that include a MTA and a DNA-damaging agent (DDA) are preferred (Table S1).…”

MPHOSPH1: A Potential Therapeutic Target for Hepatocellular Carcinoma

“…For instance, ispinesib (SB-715992, Cytokinetics and GlaxoSmithKline), the first Eg5 inhibitor to enter clinical trials, has been closed for further trials as a monotherapy due to its lack of clinical efficacy for a number of solid tumors (23)(24)(25). An explanation for the clinical failure of mitosis-specific suppressors is the much smaller proportion of mitotic cells in human tumors compared with the animal xenograft models (26). Because of the insufficient antitumor effect of monotherapy, several ongoing clinical studies have incorporated KIF inhibitors with chemotherapeutic agents including carboplatin, capecitabine, and docetaxel to explore potential synergistic effects (27).…”

Brazilin Isolated fromCaesalpinia sappanSuppresses Nuclear Envelope Reassembly by Inhibiting Barrier-to-Autointegration Factor Phosphorylation

“…Despite reliable anticancer activity, microtubule inhibitors have severe side effects. And contrary to expectation, at tolerable concentrations, microtubule regulatory protein inhibitors investigated as a substitute for microtubule blockers have displayed weak anticancer effects (Komlodi-Pasztor et al, 2012;Mitchison, 2012).…”