![Model depicting microtubule lattice repair in matching and mismatching conditions. In the precatastrophe state, MSAs stabilize depolymerizing protofilaments and inhibit depolymerization. In matching conditions, this leads to rapid repair of microtubule defects and resto-ration of microtubule growth. In mismatching conditions, lattice defects persist despite repair due to a switch in protofilament number. The presence of a defect might generate strain in the lattice, which would affect the growing microtubule end and induce catastrophe. [Adapted from PNAS 2021] imagen](/sites/default/files/2021-12/imagen-web_3.jpg)
Two new works recently published as part of international collaborations by the group of Dr. Fernando Diaz at the CIB Margarita Salas (CSIC) in the journals Developmental Cell and PNAS have delved into the molecular mechanisms of the functioning of taxanes and how the tumors develop resistance mechanisms to these.
One of the main causes of the failure of antitumor treatments is the development of resistance to them. The article published in Developmental Cell by Thakkar et al. presents the molecular mechanisms underlying one of the causes of resistance to taxane treatments: the overexpression of a truncated form of a microtubule modulator protein that blocks the access of drugs to their site of union causing resistance. Furthermore, it has been shown that inhibition of the BCR-ABL gene with imatinib prevents the expression of the truncated form of the protein, reversing the resistance and restoring the tumor's sensitivity to taxanes.
The CIB-CSIC's Structure, function and pharmacology of Cytoskeleton group has contributed to this international collaboration with the universities of Notre Dame and the Well Cornell Medical Center by determining the effects of the truncated protein on the binding of drugs to microtubules, demonstrating binding blockage concomitant with loss of drug efficacy.
On the other hand, although it is known that very low concentrations of taxanes, three orders of magnitude below that of cellular tubulin, effectively inhibit the functioning of microtubules, it is unknown how these small concentrations manage to inhibit this function by binding to a minimum fraction of cellular tubulin.
In the work published in the journal PNAS by Rai et al. as a result of the collaboration of the CIB-CSIC with the Universities of Utrecht, London, and Cambridge, it has been determined that the binding of taxanes to a single tubulin molecule in microtubules produces a structural disturbance that is transmitted along them, affecting their recognition by other proteins and altering their function. The CIB Margarita Salas group has contributed to this collaboration by determining the structure of these altered microtubules in the ALBA synchrotron (Barcelona).
References:
1.- CLIP-170S is a novel microtubule +TIP variant that confers resistance to taxanes by impairing drug-target engagement. Thakkar, P.V.; Kita, K.; del Castillo, U.; Galletti, G.; Madhukar; N.; Vila-Navarro, E.; Barasoain, I.; Goodson, H.V.; Sackett, D.; Díaz, J.F.; Lu, Y; RoyChoudhary, A.; Molina, H.; Elemento, O.; Shah, M.A.; Giannakakou, P. (2021) Developmental Cell. https://doi.org/10.1016/j.devcel.2021.09.023
2.- Lattice defects induced by microtubule stabilizing agents exert a long-range effect on microtubule growth by promoting catastrophes. Rai, A.; Liu, T.; Katrukha, E.A.; Estévez-Gallego, J.; Manka, S.W.; Paterson, I; Díaz, J.F.; Kapitein, L.C.; Moores; C and Akhmanova, A. (2021) PNAS. https://doi.org/10.1073/pnas.2112261118