Fighting tubulin-targeting anticancer drug toxicity and resistance

  1. Domenico Grieco2,3
  1. 1Institute for the Experimental Endocrinology and Oncology ‘G. Salvatore’, Italian National Council of Research, Napoli, Italy
  2. 2Ceinge-Biotecnologie Avanzate, Napoli, Italy
  3. 3Department of Molecular Medicine and Medical Biotechnologies, University of Napoli ‘Federico II’, Napoli, Italy
  1. Correspondence should be addressed to R Visconti or D Grieco; Email: r.visconti{at} or domenico.grieco{at}
  1. Figure 1

    Mechanisms of resistance to androgen deprivation therapy. Three main mechanisms of resistance to androgen deprivation therapy related to androgen receptor (AR) are depicted. Other mechanisms of resistance have been described, such as androgen-independent activation of AR mediated by oncogenic signaling (see text and Wadosky & Koochekpour 2016). (A) Castration-resistant prostate cells overexpress AR because of gene amplification; (B) point mutated ARs are constitutively active; (C) AR splice variants are ligand independent. The AR splice variant 7 (ARv7), one of the most clinically prevalent, is depicted. In any case, ARs bind to DNA, leading to a deregulated expression of androgen-target genes and, in turn, to aberrant proliferation of prostate cells. AR, androgen receptor; ARE, androgen-responsive element; DHT, dihydrotestosterone.

  2. Figure 2

    Regulation of CDK1 activity during the cell cycle In S phase, cyclin B is synthesized; however, the cyclin B/CDK1 complex is kept inactive because CDK1 is phosphorylated at the inhibitory sites threonine 14 (T14) and tyrosine 15 (Y15) by the kinases WEE1 and MYT1. At mitosis onset, the CDK1 inhibitory sites T14 and Y15 are dephosphorylated by the CDC25C phosphatase. During M phase, CDK1, in autoactivation loops, phosphorylates CDC25C and WEE1/MYT1, enhancing and inhibiting, respectively, their enzymatic activities.

  3. Figure 3

    Regulation of CDK1 activity by FCP1 at mitosis exit. During mitosis exit, the phosphatase FCP1 dephosphorylates WEE1 at threonine 239, a crucial site for the CDK1 autoactivation loop. Thus, CDK1 undergoes transient, inhibitory WEE1-dependent tyrosine 15 phosphorylation before substantial inactivation by cyclin B proteolysis.

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