Plinabulin, an inhibitor of tubulin polymerization, targets KRAS signaling through disruption of endosomal recycling

Cimino,Patrick  J.; Huang,Lan; Du,Lihua; Wu,Yanping; Bishop,Jamie; Dalsing-Hernandez,Jessica; Kotlarczyk,Kari; Gonzales,Paul; Carew,Jennifer; Nawrocki,Steffan; Jordan,Mary  Ann; Wilson,Leslie; Lloyd,G.  Kenneth; Wirsching,Hans-Georg

doi:10.3892/br.2019.1196

April-2019 Volume 10 Issue 4

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April-2019 Volume 10 Issue 4

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Article Open Access

Plinabulin, an inhibitor of tubulin polymerization, targets KRAS signaling through disruption of endosomal recycling

Authors:
- Patrick J. Cimino
- Lan Huang
- Lihua Du
- Yanping Wu
- Jamie Bishop
- Jessica Dalsing-Hernandez
- Kari Kotlarczyk
- Paul Gonzales
- Jennifer Carew
- Steffan Nawrocki
- Mary Ann Jordan
- Leslie Wilson
- G. Kenneth Lloyd
- Hans-Georg Wirsching
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Affiliations: Department of Pathology, University of Washington, Seattle, WA 98104, USA, BeyondSpring Pharmaceuticals Inc., New York City, NY 10005, USA, Biomolecular Science and Engineering, University of California, Santa Barbara, CA 93106, USA, Translational Drug Development Inc., Scottsdale, AZ 85259, USA, Institute for Drug Development, University of Texas, San Antonio, TX 78249, USA, Department of Neurology, University Hospital Zurich, CH-8091 Zurich, Switzerland

Copyright: © Cimino et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Pages: 218-224
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Published online on: March 5, 2019

https://doi.org/10.3892/br.2019.1196
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Abstract

Constitutive activation of Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogenic event in certain types of human cancer and is associated with poor patient survival. Small molecule signaling inhibitors have improved the clinical outcomes of patients with various cancer types but attempts to target KRAS have been unsuccessful. Plinabulin represents a novel class of agents that inhibit tubulin polymerization with a favorable safety profile in clinical trials. In the present study, the potency of plinabulin to inhibit tubulin polymerization and growth of KRAS‑driven cancer cells was characterized. In vivo efficacy of plinabulin was tested in two different mouse models; one being the RCAS/t‑va gene transfer system and the other being a xenograft model. In vitro cell culture tubulin polymerization assays were used to complement the mouse models. There was improved survival in a KRAS‑driven mouse gene transfer glioma model, but lack of benefit in a similar model, without constitutively active KRAS, which supports the notion of a KRAS‑specific effect. This survival benefit was mediated, at least in part, by the ability of plinabulin to inhibit tubulin polymerization and disrupt endosomal recycling. It was proposed a mechanism of compromised endosomal recycling of displaced KRAS through targeting microtubules that yields inhibition of protein kinase B, but not extracellular signal regulated kinase (ERK) signaling, therefore lending rationale to combination treatments of tubulin‑ and ERK‑targeting agents in KRAS‑driven cancer.

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Journals

International Journal of Molecular Medicine

International Journal of Oncology

Molecular Medicine Reports

Oncology Reports

Experimental and Therapeutic Medicine

Oncology Letters

Biomedical Reports

Molecular and Clinical Oncology

World Academy of Sciences Journal

International Journal of Functional Nutrition

International Journal of Epigenetics

Medicine International

Plinabulin, an inhibitor of tubulin polymerization, targets KRAS signaling through disruption of endosomal recycling

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