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

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)34561-34572
Number of pages12
JournalOncotarget
Volume6
Issue number33
DOIs
Publication statusPublished - 2015
Externally publishedYes

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Mitogen-Activated Protein Kinase Kinases
Heterografts
Colorectal Neoplasms
Cell Line
Neoplasms
Growth
lissamine rhodamine B
TAK 733
Genotype
Allosteric Site
Linear Models
Mutation

Keywords

  • Colorectal cancer
  • MEK
  • Patient derived xenografts
  • TAK-733

ASJC Scopus subject areas

  • Oncology

Cite this

Lieu, C. H., Klauck, P. J., Henthorn, P. K., Tentler, J. J., Tan, A-C., Spreafico, A., ... Gail Eckhardt, S. (2015). Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts. Oncotarget, 6(33), 34561-34572. https://doi.org/10.18632/oncotarget.5949

Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts. / Lieu, Christopher H.; Klauck, Peter J.; Henthorn, Patrick K.; Tentler, John J.; Tan, Aik-Choon; Spreafico, Anna; Selby, Heather M.; Britt, Blair C.; Bagby, Stacey M.; Arcaroli, John J.; Messersmith, Wells A.; Pitts, Todd M.; Gail Eckhardt, S.

In: Oncotarget, Vol. 6, No. 33, 2015, p. 34561-34572.

Research output: Contribution to journalArticle

Lieu, CH, Klauck, PJ, Henthorn, PK, Tentler, JJ, Tan, A-C, Spreafico, A, Selby, HM, Britt, BC, Bagby, SM, Arcaroli, JJ, Messersmith, WA, Pitts, TM & Gail Eckhardt, S 2015, 'Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts', Oncotarget, vol. 6, no. 33, pp. 34561-34572. https://doi.org/10.18632/oncotarget.5949
Lieu, Christopher H. ; Klauck, Peter J. ; Henthorn, Patrick K. ; Tentler, John J. ; Tan, Aik-Choon ; Spreafico, Anna ; Selby, Heather M. ; Britt, Blair C. ; Bagby, Stacey M. ; Arcaroli, John J. ; Messersmith, Wells A. ; Pitts, Todd M. ; Gail Eckhardt, S. / Antitumor activity of a potent MEK inhibitor, TAK-733, against colorectal cancer cell lines and patient derived xenografts. In: Oncotarget. 2015 ; Vol. 6, No. 33. pp. 34561-34572.
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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.",
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AU - Klauck, Peter J.

AU - Henthorn, Patrick K.

AU - Tentler, John J.

AU - Tan, Aik-Choon

AU - Spreafico, Anna

AU - Selby, Heather M.

AU - Britt, Blair C.

AU - Bagby, Stacey M.

AU - Arcaroli, John J.

AU - Messersmith, Wells A.

AU - Pitts, Todd M.

AU - Gail Eckhardt, S.

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