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Vav2 pharmaco-mimetic mice reveal the therapeutic value and caveats of the catalytic inactivation of a Rho exchange factor

Oncogene volume 39, pages 5098–5111 (2020)Cite this article

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Abstract

The current paradigm holds that the inhibition of Rho guanosine nucleotide exchange factors (GEFs), the enzymes that stimulate Rho GTPases, can be a valuable therapeutic strategy to treat Rho-dependent tumors. However, formal validation of this idea using in vivo models is still missing. In this context, it is worth remembering that many Rho GEFs can mediate both catalysis-dependent and independent responses, thus raising the possibility that the inhibition of their catalytic activities might not be sufficient per se to block tumorigenic processes. On the other hand, the inhibition of these enzymes can trigger collateral side effects that could preclude the practical implementation of anti-GEF therapies. To address those issues, we have generated mouse models to mimic the effect of the systemic application of an inhibitor for the catalytic activity of the Rho GEF Vav2 at the organismal level. Our results indicate that lowering the catalytic activity of Vav2 below specific thresholds is sufficient to block skin tumor initiation, promotion, and progression. They also reveal that the negative side effects typically induced by the loss of Vav2 can be bypassed depending on the overall level of Vav2 inhibition achieved in vivo. These data underscore the pros and cons of anti-Rho GEF therapies for cancer treatment. They also support the idea that Vav2 could represent a viable drug target.

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Fig. 1: Characterization of the L332A mutation of the Vav2 DH domain.
Fig. 2: Description and basic characterization of the Vav2L332A knock-in strain and other mouse models used in this study.
Fig. 3: Partial impairment of Vav2 GEF activity blocks skin tumorigenesis.
Fig. 4: The level of Vav2 catalytic activity inhibition determines the generation of negative side effects in mice.

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Acknowledgements

We thank M. Blazquez for lab work and CIC facilities’ personnel for technical assistance. XRB is supported by grants from Worldwide Cancer Research (14-1248), the Castilla-León Government (CSI252P18, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (RTI2018-096481-B-I00), and the Spanish Association against Cancer (GC16173472GARC). XRB’s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01). SF, SR-F, and LFL-M contracts have been supported by funding from the MSI (SF, BES-2010-031386; SR-F, BES-2013-063573), the Spanish Ministry of Universities (LFL-M, FPU13/02923), and the CLC-2017-01 grant (SR-F and LFL-M). JR-V has been supported by the CIBERONC and, currently, by the Spanish Association against Cancer. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund.

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Author notes

  1. Salvatore Fabbiano

    Present address: Cell Press Editorial Office, Cambrige MA02139, USA

  2. These authors contributed equally: L. Francisco Lorenzo-Martín, Sonia Rodríguez-Fdez, Salvatore Fabbiano

Authors and Affiliations

  1. Centro de Investigación del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain

    L. Francisco Lorenzo-Martín, Sonia Rodríguez-Fdez, Salvatore Fabbiano, Antonio Abad, María C. García-Macías, Mercedes Dosil, Myriam Cuadrado, Javier Robles-Valero & Xosé R. Bustelo

  2. Instituto de Biología Molecular y Celular del Cáncer, CSIC-University of Salamanca, 37007, Salamanca, Spain

    L. Francisco Lorenzo-Martín, Sonia Rodríguez-Fdez, Salvatore Fabbiano, Antonio Abad, María C. García-Macías, Mercedes Dosil, Myriam Cuadrado, Javier Robles-Valero & Xosé R. Bustelo

  3. Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), CSIC-University of Salamanca, 37007, Salamanca, Spain

    L. Francisco Lorenzo-Martín, Sonia Rodríguez-Fdez, Antonio Abad, Mercedes Dosil, Myriam Cuadrado, Javier Robles-Valero & Xosé R. Bustelo

  4. Departamento de Bioquímica y Biología Molecular, School of Pharmacy, University of Salamanca, 37007, Salamanca, Spain

    Mercedes Dosil

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  1. L. Francisco Lorenzo-Martín
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Contributions

LFL-M participated in all the experiments shown in Figs. 3, 4b–e, in data analyses, and in artwork design. SF carried out the experiments shown in Figs. 1, 4a–e, analyzed the data, and contributed to artwork design. SR-F carried out the experiments shown in Figs. 2c–f, 4f, g, analyzed the data, and contributed to artwork design. AA helped in mouse work (crosses, genotyping, carcinogenesis experiments). MCG-M carried out the histopathological analyses of tumors. MD contributed to data analysis and paper writing. MC and JR-V contributed to the characterization of different phenotypic parameters of Vav2L332A mice. XRB conceived the work, analyzed data, wrote the paper, and performed the final editing of figures.

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Correspondence to Xosé R. Bustelo.

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Animal work was done according to protocols approved by the Bioethics committee of Salamanca University.

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Lorenzo-Martín, L.F., Rodríguez-Fdez, S., Fabbiano, S. et al. Vav2 pharmaco-mimetic mice reveal the therapeutic value and caveats of the catalytic inactivation of a Rho exchange factor. Oncogene 39, 5098–5111 (2020). https://doi.org/10.1038/s41388-020-1353-x

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