Tuning microtubule dynamics to enhance cancer therapy by modulating FER-mediated CRMP2 phosphorylation

Yiyan Zheng, Ritika Sethi, Lingegowda S. Mangala, Charlotte Taylor, Juliet Goldsmith, Ming Wang, Kenta Masuda, Eli M. Carrami, David Mannion, Fabrizio Miranda, Sandra Herrero-Gonzalez, Karin Hellner, Fiona Chen, Abdulkhaliq Alsaadi, Ashwag Albukhari, Donatien Chedom Fotso, Christopher Yau, Dahai Jiang, Sunila Pradeep, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Stefan Knapp, Nathanael S. Gray, Leticia Campo, Kevin A. Myers, Sunanda Dhar, David Ferguson, Robert C. Bast, Anil K. Sood, Frank von Delft and Ahmed Ashour Ahmed ()
Additional contact information
Yiyan Zheng: University of Oxford
Ritika Sethi: University of Oxford
Lingegowda S. Mangala: The University of Texas MD Anderson Cancer Center
Charlotte Taylor: University of Oxford
Juliet Goldsmith: University of Oxford
Ming Wang: University of Oxford
Kenta Masuda: University of Oxford
Eli M. Carrami: University of Oxford
David Mannion: University of Oxford
Fabrizio Miranda: University of Oxford
Sandra Herrero-Gonzalez: University of Oxford
Karin Hellner: University of Oxford
Fiona Chen: University of Oxford
Abdulkhaliq Alsaadi: University of Oxford
Ashwag Albukhari: University of Oxford
Donatien Chedom Fotso: University of Oxford
Christopher Yau: Wellcome Trust Centre for Human Genetics and NIHR Biomedical Research Centre
Dahai Jiang: The University of Texas MD Anderson Cancer Center
Sunila Pradeep: The University of Texas MD Anderson Cancer Center
Cristian Rodriguez-Aguayo: The University of Texas MD Anderson Cancer Center
Gabriel Lopez-Berestein: The University of Texas MD Anderson Cancer Center
Stefan Knapp: University of Oxford
Nathanael S. Gray: Harvard Medical School
Leticia Campo: University of Oxford
Kevin A. Myers: University of Oxford
Sunanda Dhar: Oxford University Hospitals
David Ferguson: Oxford University Hospitals
Robert C. Bast: University of Texas MD Anderson Cancer Center
Anil K. Sood: The University of Texas MD Anderson Cancer Center
Frank von Delft: University of Oxford
Ahmed Ashour Ahmed: University of Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Though used widely in cancer therapy, paclitaxel only elicits a response in a fraction of patients. A strong determinant of paclitaxel tumor response is the state of microtubule dynamic instability. However, whether the manipulation of this physiological process can be controlled to enhance paclitaxel response has not been tested. Here, we show a previously unrecognized role of the microtubule-associated protein CRMP2 in inducing microtubule bundling through its carboxy terminus. This activity is significantly decreased when the FER tyrosine kinase phosphorylates CRMP2 at Y479 and Y499. The crystal structures of wild-type CRMP2 and CRMP2-Y479E reveal how mimicking phosphorylation prevents tetramerization of CRMP2. Depletion of FER or reducing its catalytic activity using sub-therapeutic doses of inhibitors increases paclitaxel-induced microtubule stability and cytotoxicity in ovarian cancer cells and in vivo. This work provides a rationale for inhibiting FER-mediated CRMP2 phosphorylation to enhance paclitaxel on-target activity for cancer therapy.

Date: 2018
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DOI: 10.1038/s41467-017-02811-7

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