Targeting LIM kinases in taxane resistant tumors

Microtubule stabilizing drugs such as taxanes have proven fairly effective for treating solid tumors, but the mechanism by which these drugs treat cancer is still unsolved. Intratumor imaging, showing that the cell proliferation rate is low in many chemosensitive human cancers, has challenged the dogma that the cytotoxicity of such compounds is the result of their effect on rapidly dividing cells [1]. Moreover, attempts to develop selective antimitotic cancer drugs that inhibit proteins mainly involved in mitosis have failed. These findings suggest that taxanes may target other microtubule-based mechanisms in addition to mitosis, in cancer cells as well as in cells of the tumor environment, or that their therapeutic effect results from a microtubule independent targeting [1, 2]. In addition, taxanes cause severe side effects, including myelosuppression and neurotoxicity, presumably due to the general perturbation of microtubule functions in normal cells. Finally, the fact that many cancers are inherently resistant to taxane chemotherapy or become so during prolonged treatment make these drugs less than ideal. The search for next generation microtubule stabilizing drugs with increased efficacy is thus intense. Several strategies have been proposed for the development of potentially more effective and less toxic anticancer drugs. One approach is to find drugs that target non-essential proteins, such as microtubule regulators. If such a target would be more active in cancer cells, or centrally involved in cancer aggressiveness, its inhibition would improve drug selectivity for tumors over normal tissue and contribute to a greater therapeutic window. LIM Kinases (LIMKs) are enzymes whose activity is elevated in cancers compared to normal tissue. LIMKs regulate the architecture of the actin cytoskeleton by phosphorylation and inactivation of actin depolymerization factors of the ADF/cofilin family. Independently of this effect on actin microfilament dynamics, LIMKs also regulate microtubule dynamics, but whether this regulation occurs through a direct binding of LIMK to microtubules or through phosphorylation of an associated protein is still unknown [3, 4]. When LIMKs are inhibited, microtubules are stabilized and actin microfilaments are severed. Owing to their stabilizing effect on microtubules, LIMK inhibitors may provide a therapeutic strategy to treat taxane-resistant cancers. A highly selective LIMK inhibitor, Pyr1, has been previously characterized by Prudent et al [4]. Although ATP-competitive, Pyr1 inhibits only LIMKs out of 110 kinases tested. When applied on cells, Pyr1 stabilizes microtubules, induces a moderate cell cycle arrest at the S-G2/M phase and blocks actin microfilament dynamics and cell motility. Anticancer …