Abstract A184: Activity of plinabulin in tumor models with Kras mutations

• Published in: Molecular cancer therapeutics 2015-12, Vol.14 (12_Supplement_2), p.A184-A184
• Main Authors: Lloyd, George Kenneth, Du, Lihua, Lee, Gloria, Dalsing-Hernandez, Jessica, Kotlarczyk, Kari, Gonzales, Paul, Nawrocki, Steffan, Carew, Jennifer, Huang, Lan
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-15-A184

Kras mutations, particularly at codons 12 and 13, are reported to occur in up to one-third of human cancer cells and are considered to be undruggable targets (Stoize et al, 2015). These mutations are especially prevalent in NSCLC and CRC. Plinabulin is a new chemical entity in Phase 3, with a multi-faceted mechanism of action, including anti-angiogenesis, inhibition of tubulin polymerization and activation of JNK, which is downstream of the Kras pathway. The combination of these vascular mechanisms together with activity downstream from Kras, suggests that plinabulin could express anti-tumor activity in the presence of Kras mutations. The present report summarizes the findings with plinabulin on tumors with Kras mutations (p.12V, p.12D, p.D153V, p.G12A, p.G12C, p.G12D, p.G12V or p.G13D) in vitro and in vivo. In vitro, plinabulin was very potent (IC50 7-33 nM) as a cytotoxic agent against CRC cell lines containing a Kras mutation at p.G13D (LoVo, HCT-15, HCT116) or a BRAF + P53 mutation (HT-29) and against multiple myeloma cell lines (Singh et al, Blood, 2010) with either Nras or p.G12A mutations (IC50