Oncotarget

Research Papers:

Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts

Christopher H. Lieu _, Peter J. Klauck, Patrick K. Henthorn, John J. Tentler, Aik-Choon Tan, Anna Spreafico, Heather M. Selby, Blair C. Britt, Stacey M. Bagby, John J. Arcaroli, Wells A. Messersmith, Todd M. Pitts, S. Gail Eckhardt

PDF |  HTML  |  Supplementary Files  |  Author Information  |  Order a Reprint

Oncotarget. 2015; 6:34561-34572. https://doi.org/10.18632/oncotarget.5949

Metrics: PDF 552 views  |   HTML 505 views  |   ?  


Abstract

Christopher H. Lieu1, Peter J. Klauck1, Patrick K. Henthorn1, John J. Tentler1, Aik-Choon Tan1, Anna Spreafico1, Heather M. Selby1, Blair C. Britt1, Stacey M. Bagby1, John J. Arcaroli1, Wells A. Messersmith1, Todd M. Pitts1 and S. Gail Eckhardt1

1 Department of Medicine, Division of Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

Correspondence to:

Christopher H. Lieu, email:

Keywords: MEK, colorectal cancer, patient derived xenografts, TAK-733

Received: August 09, 2015 Accepted: September 05, 2015 Published: October 01, 2015

Abstract

Background: CRC is a significant cause of cancer mortality, and new therapies are needed for patients with advanced disease. TAK-733 is a highly potent and selective investigational novel MEK allosteric site inhibitor.

Materials and Methods: In a preclinical study of TAK-733, a panel of CRC cell lines were exposed to varying concentrations of the agent for 72 hours followed by a sulforhodamine B assay. Twenty patient-derived colorectal cancer xenografts were then treated with TAK-733 in vivo. Tumor growth inhibition index (TGII) was assessed to evaluate the sensitivity of the CRC explants to TAK-733 while linear regression was utilized to investigate the predictive effects of genotype on the TGII of explants.

Results: Fifty-four CRC cell lines were exposed to TAK-733, while 42 cell lines were deemed sensitive across a broad range of mutations. Eighty-two percent of the cell lines within the sensitive subset were BRAF or KRAS/NRAS mutant, whereas 80% of the cell lines within the sensitive subset were PIK3CA WT. Twenty patient-derived human tumor CRC explants were then treated with TAK-733. In total, 15 primary human tumor explants were found to be sensitive to TAK-733 (TGII ≤ 20%), including 9 primary human tumor explants that exhibited tumor regression (TGII > 100%). Explants with a BRAF/KRAS/NRAS mutant and PIK3CA wild-type genotype demonstrated increased sensitivity to TAK-733 with a median TGII of -6%. MEK-response gene signatures also correlated with responsiveness to TAK-733 in KRAS-mutant CRC.

Conclusions: The MEK inhibitor TAK-733 demonstrated robust antitumor activity against CRC cell lines and patient-derived tumor explants. While the preclinical activity observed in this study was considerable, single-agent efficacy in the clinic has been limited in CRC, supporting the use of these models in an iterative manner to elucidate resistance mechanisms that can guide rational combination strategies.

Author Information

Christopher H. Lieu
Primary Contact  _

Peter J. Klauck

Patrick K. Henthorn

John J. Tentler

Aik-Choon Tan

Anna Spreafico

Heather M. Selby

Blair C. Britt

Stacey M. Bagby

John J. Arcaroli

Wells A. Messersmith

Todd M. Pitts

S. Gail Eckhardt


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 5949