Dichotomous role of microtubule associated protein tau as a biomarker of response to and a target for increasing efficacy of taxane treatment in cancers of epithelial origin

Abstract

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.

Keywords: 5-Fluorouracil (PubChem CID: 3385); Alzheimer’s disease; Biomarker; Breast cancer; Carboplatin (PubChem CID: 426756); Chemoresistance; Cisplatin (PubChem CID: 5702198); Cyclophosphamide (PubChem CID: 2907); Docetaxel (PubChem CID: 148124); Doxorubicin (PubChem CID: 31703); Etoposide (PubChem CID: 36462); Ovarian cancer; Paclitaxel (PubChem CID: 36314); Tamoxifen (PubChem CID: 2733526); Taxane; Topotecan (PubChem CID: 60700).

FIGURE 1.

Structure of tau isoforms. The transcriptional organization of six low molecular weight human brain-specific tau isoforms and one high molecular weight rodent peripheral nervous system-specific tau isoform with constitutively expressed exons 1, 4, 5, 7, 9, 11, 12, and 13, and alternatively spliced exons 2, 3, 4A, 6, and 10 is shown. Isoforms, their abbreviations, and lengths, as well as the domain architecture are indicated.