University of Illinois at Chicago, College of Pharmacy, Department of Pharmaceutical Sciences, 833 South Wood Street, Chicago, IL 60612, USA.
Pharmacol Res. 2021 Jun;168:105585. doi: 10.1016/j.phrs.2021.105585. Epub 2021 Mar 30.
Cancer is the second leading cause of death worldwide, and the World Health Organization estimates that one in six deaths globally is due to cancer. Chemotherapy is one of the major modalities used to treat advanced cancers and their metastasis. However, the existence of acquired and intrinsic resistance to anti-cancer drugs often diminishes their therapeutic effect. In order to pre-select patients who could benefit the most from these treatments, the efforts of many research groups have been focused on identification of biomarkers of therapy response. Taxanes paclitaxel (Taxol) and docetaxel (Taxotere) have been introduced as chemotherapy for treatment of cancers of ovary in 1992 and breast in 1996, respectively. Since then, clinical use of taxanes has expanded to include lung, prostate, gastric, head and neck, esophageal, pancreatic, and cervical cancers, as well as Kaposi sarcoma. Several independent molecular mechanisms have been shown to support taxane chemoresistance. One such mechanism is dependent on microtubule associated protein tau. Tau binds to the same site on the inner side of the microtubules that is also occupied by paclitaxel or docetaxel, and several studies have demonstrated that low/no tau expression significantly correlated with better response to the taxane treatment, suggesting that levels of tau expression could have a predictive value in pre-selecting patient cohorts that are likely to benefit from the treatment. However, several other studies have found no correlation between tau expression and taxane response, introducing a controversy and precluding its wide use as a predictive biomarker. Based on the knowledge of tau biology accumulated thus far, in this review we attempt to critically analyze the studies that evaluated tau as a biomarker of taxane response. Further, we identify yet unknown aspects of tau biology understanding of which is necessary for improvement of development of tau as a biomarker of response and a target for increasing response to taxane treatment.
癌症是全球第二大死亡原因，世界卫生组织估计，全球每六例死亡中就有一例归因于癌症。化疗是治疗晚期癌症及其转移的主要方法之一。然而，癌症药物的获得性和固有耐药性的存在往往会降低其治疗效果。为了预先选择最有可能从这些治疗中受益的患者，许多研究小组的努力都集中在鉴定治疗反应的生物标志物上。紫杉醇（Taxol）和多西紫杉醇（Taxotere）于 1992 年和 1996 年分别被引入作为治疗卵巢癌和乳腺癌的化疗药物。从那时起，紫杉烷的临床应用已经扩展到包括肺癌、前列腺癌、胃癌、头颈部癌、食管癌、胰腺癌和宫颈癌以及卡波西肉瘤。已经有几个独立的分子机制被证明支持紫杉烷的化疗耐药性。其中一个机制依赖于微管相关蛋白 tau。Tau 结合到微管内侧与紫杉醇或多西紫杉醇相同的位置，几项研究表明，低/无 tau 表达与对紫杉烷治疗的更好反应显著相关，这表明 tau 表达水平可能具有预测价值，可以预先选择可能从治疗中受益的患者群体。然而，其他几项研究发现 tau 表达与紫杉烷反应之间没有相关性，这引发了争议，并排除了其作为预测生物标志物的广泛应用。基于迄今为止积累的 tau 生物学知识，在这篇综述中，我们试图批判性地分析评估 tau 作为紫杉烷反应生物标志物的研究。此外，我们确定了 tau 生物学理解中尚未被认识的方面，这些方面对于改进 tau 作为反应生物标志物和增加紫杉烷治疗反应的靶标的发展是必要的。
