Abstract C191: Preclinical investigation of the antitumor efficacy in lung cancer of Y15, a novel focal adhesion kinase inhibitor

• Published in: Molecular cancer therapeutics Vol. 10; no. 11_Supplement; p. C191
• Main Authors: Dy, Grace K., Shao, Huanjie, Ho, Baotran, Yemma, Michael, Adjei, Alex, Golubovskaya, Vita, Cance, William
• Format: Journal Article
• Language: English
• Published: 12-11-2011
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-11-C191

Introduction: Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that associates with a number of cell adhesion components, such as integrins, paxillin and talin, as well as with various signaling proteins such as phosphatidylinositol 3-kinase (PI3K) and the Src family of protein kinases. It thus plays an important role in cell motility, invasion, growth and cell survival. Y15 (1,2,4,5-benzentetraamine tetra hydrochloride) is a small molecule that inhibits FAK autophosphorylation by selectively targeting the Y397 phosphorylation site of FAK. It has shown activity against breast, colon and pancreatic cancers. We herein present data in lung cancer.
Methods: Various lung cancer cell lines as well as minimally passaged patient-derived tumor (containing PIK3CA mutation E545K) propagated in vitro were treated with escalating doses of Y15 or DMSO for 72 hours to evaluate single-agent activity. Cell lines were also treated with cytotoxic agents (cisplatin, gemcitabine, pemetrexed, paclitaxel) in combination with escalating doses of Y15. Cellular viability was assessed by trypan blue exclusion assay and colony formation assay. For in vivo experiments, selected cell lines were implanted into nude mice and vehicle versus Y15 treatment, via either intraperitoneal or oral gavage administration, once daily was started when tumors reached a mean volume of 50–60 mm3. Western blot will be performed to investigate alterations in the activity of various signaling proteins.
Results: Y15 exhibited time and dose-dependent cell death in 6 out of 9 lung cancer cell lines tested. Activity was demonstrated beginning at 4 uM dose, with almost 100% cell kill demonstrated at 10 uM dose. There was also corresponding dose-dependent loss of clonogenic ability starting at 1 uM dose in sensitive cell lines. In addition, Y15 enhanced paclitaxel-induced cell death. Mice treated with Y15 at 100 mg/kg oral gavage administration showed reduced tumor growth compared to control mice.
Conclusion: Y15 demonstrates promising antitumor efficacy against various non-small cell lung cancer cell lines. Further development of this agent in lung cancer is warranted.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C191.