Role of the chemotherapy resistance related tubulin isotype beta-III in the microtubule structure and its modulation by chemotherapeutic drugs.

Microtubules (MTs) are nanomachines composed of tubulin and microtubule associated
proteins (MAPs). There exist different layers of complexity to regulate this apparently simple
structure. The first level of regulation is based on the chemical state of the tubulin dimer, which is
determined by the nucleotide bound. On top of the nucleotide regulation lays the “tubulin code”,
formed by the expression of different alpha- and beta tubulin isotypes. These two major levels of
regulation are able to call and affect the interaction of MAPs, which regulate MT dynamics and
function mechanisms. Finally, we of small compounds, that bind either to tubulin or MT chemically
regulate MT formation and dynamics.
Given its essential role, MTs have become a successful target for chemotherapy. While first magic
bullets targeting cancer were discovered in the 60´s, lowering the death toll of child leukemias from
95 to 5%, paclitaxel and docetaxel (wide spectrum drugs targeting solid tumours), become first line
therapeutic options for breast, lung and ovarian cancer in the 90´s. Unfortunately, one of the major
drawbacks of paclitaxel and docetaxel treatments is the development of resistance resulting from the
overexpression of the beta3 isotype. Since MT function is regulated through structural changes
which arise from the tubulin structural plasticity on response to the chemical condition of the
nucleotide site and the isotype composition, specially beta3, it is reasonable to suggest that beta3
overexpression affects the structural response of MTs to paclitaxel and docetaxel limiting their
effectivity.
Based on the results obtained from previous proposals, and especially those we expect to have on
our next beam time 2023027372, we expect to understand how isotype composition affect the
structural signals on the microtubule surface and their modulation by chemotherapeutic drugs.
Being the ultimate goal to understand the role of beta3 tubulin isotype in the resistance against
taxanes.