New insights into mechanisms of resistance to microtubule inhibitors

Abstract

Mechanisms to explain tumor cell resistance to drugs that target the microtubule cytoskeleton have relied on the assumption that the drugs act either to suppress microtubule dynamics or to perturb the balance between assembled and nonassembled tubulin. Recently, however, it was found that these drugs also alter the stability of microtubule attachment to centrosomes, and do so at the same concentrations that are needed to inhibit cell division. Based on this new information, a new model is presented that explains resistance resulting from a variety of molecular changes that have been reported in the literature. The improved understanding of drug action and resistance has important implications for chemotherapy with these agents.

Fig. 1

Relationship between microtubule polymer levels and drug resistance. The model assumes that cells remain viable within a small range of polymer levels denoted by the dashed lines, but they experience toxicity (failure to divide) outside of that range. Drugs like colcemid (Cmd) become toxic at concentrations that lower polymer levels beneath the lower limit; drugs like paclitaxel (Ptx) become toxic at concentrations that raise polymer levels beyond the upper limit. Drug resistance mutations move the polymer levels in a direction that opposes the selecting drug (paclitaxel resistance (Ptx^R) to lower levels; colcemid resistance (Cmd^R) to higher levels). When the mutations are strong enough to move the polymer levels into the toxic zones, drug dependence (Ptx^D; Cmd^D) occurs.

Fig. 2

Microtubule detachment and drug resistance. This model assumes that a normal balance of attached and non-attached microtubules is needed for normal spindle function and successful cell division. Drugs like colcemid (Cmd), or tubulin mutations that produce paclitaxel resistance (Ptx^R) or dependence (Ptx^D), increase the frequency of detachment and disrupt spindle assembly and function. Drugs like paclitaxel (Ptx), or mutations that produce colcemid resistance (Cmd^R) or dependence (Cmd^D), decrease the frequency of detachment and thereby also disrupt spindle assembly and function. There is evidence to indicate that MCAK is involved in microtubule detachment, thus explaining why overproduction of the protein confers resistance to drugs like paclitaxel that inhibit detachment. The diagram depicts microtubules bound to and detaching from one of the two spindle poles.