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

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

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)218-224
Number of pages7
JournalBiomedical Reports
Volume10
Issue number4
DOIs
StatePublished - Apr 2019
Externally publishedYes

Keywords

  • Cancer
  • Endosome
  • Kirsten rat sarcoma viral oncogene homolog
  • Plinabulin
  • Tubulin

ASJC Scopus subject areas

  • General Neuroscience
  • General Biochemistry, Genetics and Molecular Biology
  • Pharmacology, Toxicology and Pharmaceutics(all)

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