Looking at Drug Resistance Mechanisms for Microtubule Interacting Drugs: Does TUBB3 Work?

Abstract

Vinca alkaloids and taxanes represent the mainstay of medical treatment of hematological and solid tumors. Unfortunately, a major clinical problem with these agents is drug resistance. Although a plethora of mechanisms of drug resistance have been described, only a few of them have been validated in clinical trials. Among these, the one involving the protein TUBB3 seems to represent a promising target for studying drug resistance. In fact, it seems that this protein is a factor promoting cell survival and represents an endogenous element of an inherent drug-resistance program built into cells to counteract the activity of microtubule-interacting drugs. Its pivotal role has been ascertained in clinical trials in lung, breast, and ovarian cancer, three diseases that can be successfully treated with microtubule-interacting drugs. Although TUBB3 is probably not a unique factor in drug resistance, the hope is that direct targeting of this protein will increase the response to microtubule-interacting drugs, thereby overcoming an important element in the growth of drug resistance.

Elevated expression of erbB3 confers paclitaxel resistance in erbB2-overexpressing breast cancer cells via upregulation of Survivin

“…Although several studies indicate that elevated expression of TUBB3 may result in therapeutic resistance to microtubule-targeting agents in many cancers (Ferlini et al, 2007;Seve and Dumontet, 2008), we saw no change in TUBB3 levels under our experimental conditions (data not shown). In addition, overexpression of erbB3 with either stable clones or transient transfection did not alter the expression levels of C-X-C chemokine Figure 1 Elevated expression of erbB3 via stable transfection induces Akt activation and attenuates paclitaxel cyototoxicity in erbB2-overexpressing breast cancer cells.…”

“…Changes in b-tubulin isotype expression with a switch from class I to III and overexpression of TXR1 (taxolresistance gene 1) lead to paclitaxel resistance (van Amerongen and Berns, 2006;Ferlini et al, 2007). Although we did not observe any changes in TUBB3 levels upon manipulation of erbB3 expression in our experimental conditions, there is no report showing whether erbB3 expression may regulate tyrosinaserelated protein 1 expression.…”

“…Although the taxanes, paclitaxel and docetaxel, have emerged as critical drugs in the treatment of breast cancer patients, acquired and intrinsic resistance to taxanes currently represents a significant clinical problem (Saloustros et al, 2008;Morris and Fornier, 2009). Although several molecular mechanisms contributing to paclitaxel resistance have been proposed (Orr et al, 2003;Ferlini et al, 2007), a series of studies demonstrates that overexpression of erbB2 inhibits paclitaxel-induced apoptosis in breast cancer cells (Yu et al, 1996(Yu et al, , 1998Tan et al, 2002). However, the role of erbB3 in paclitaxel resistance remains unclear.…”

Combining Emerging Agents in Advanced Breast Cancer

“…In some cases, drug resistance may be a manifestation of tumor survival responses mediated through various cellular mechanisms [11]. Preclinical evidence suggests that hypoxia, glucose deprivation, or possibly other cellular stress stimuli in the tumor microenvironment may boost expression of the class III isoform of tubulin ␤-3 chain (TUBB3) and decrease expression of other ␤-tubulin isoforms to which taxanes can bind [11,12].…”

“…In some cases, drug resistance may be a manifestation of tumor survival responses mediated through various cellular mechanisms [11]. Preclinical evidence suggests that hypoxia, glucose deprivation, or possibly other cellular stress stimuli in the tumor microenvironment may boost expression of the class III isoform of tubulin ␤-3 chain (TUBB3) and decrease expression of other ␤-tubulin isoforms to which taxanes can bind [11,12]. Additionally, potential involvement of multiple cell survival pathways and differences in intratumoral drug delivery and concentration are some of the possible reasons behind an observed clinical trend: patients who had previous success with an agent in one class may have an inconsistent response rate to newer agents in the same class (e.g., nanoparticle albumin-bound [nab]-paclitaxel, paclitaxel poliglumex, and larotaxel in the taxane class [13] and vinflunine [14] in the vinca alkaloid class).…”