Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models

Sara A. Flanigan, Todd M. Pitts, Timothy P. Newton, Gillian N. Kulikowski, Aik-Choon Tan, Martine C. McManus, Anna Spreafico, Maria I. Kachaeva, Heather M. Selby, John J. Tentler, S. Gail Eckhardt, Stephen Leong

Research output: Contribution to journalArticle

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Abstract

Purpose: Results from clinical trials involving resistance to molecularly targeted therapies have revealed the importance of rational single-agent and combination treatment strategies. In this study, we tested the efficacy of a type 1 insulin-like growth factor receptor (IGF1R)/insulin receptor (IR) tyrosine kinase inhibitor, OSI-906, in combination with a mitogen-activated protein (MAP)-ERK kinase (MEK) 1/2 inhibitor based on evidence that the MAP kinase pathway was upregulated in colorectal cancer cell lines that were resistant to OSI-906. Experimental Design: The antiproliferative effects of OSI-906 and the MEK 1/2 inhibitor U0126 were analyzed both as single agents and in combination in 13 colorectal cancer cell lines in vitro. Apoptosis, downstream effector proteins, and cell cycle were also assessed. In addition, the efficacy of OSI-906 combined with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886) was evaluated in vivo using human colorectal cancer xenograft models. Results: The combination of OSI-906 and U0126 resulted in synergistic effects in 11 of 13 colorectal cancer cell lines tested. This synergy was variably associated with apoptosis or cell-cycle arrest in addition to molecular effects on prosurvival pathways. The synergy was also reflected in the in vivo xenograft studies following treatment with the combination of OSI-906 and selumetinib. Conclusions: Results from this study demonstrate synergistic antiproliferative effects in response to the combination of OSI-906 with an MEK 1/2 inhibitorin colorectal cancer cell line models both in vitro and in vivo, which supports the rational combination of OSI-906 with an MEK inhibitor in patients with colorectal cancer.

Original languageEnglish
Pages (from-to)6219-6229
Number of pages11
JournalClinical Cancer Research
Volume19
Issue number22
DOIs
Publication statusPublished - 2013 Nov 15
Externally publishedYes

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Insulin Receptor
Mitogen-Activated Protein Kinase Kinases
Insulin Resistance
Colorectal Neoplasms
Cell Line
Mitogen-Activated Protein Kinases
Heterografts
Apoptosis
Cell Cycle Proteins
IGF Type 1 Receptor
3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
Cell Cycle Checkpoints
Research Design
Clinical Trials
AZD 6244
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Flanigan, S. A., Pitts, T. M., Newton, T. P., Kulikowski, G. N., Tan, A-C., McManus, M. C., ... Leong, S. (2013). Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models. Clinical Cancer Research, 19(22), 6219-6229. https://doi.org/10.1158/1078-0432.CCR-13-0145

Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models. / Flanigan, Sara A.; Pitts, Todd M.; Newton, Timothy P.; Kulikowski, Gillian N.; Tan, Aik-Choon; McManus, Martine C.; Spreafico, Anna; Kachaeva, Maria I.; Selby, Heather M.; Tentler, John J.; Eckhardt, S. Gail; Leong, Stephen.

In: Clinical Cancer Research, Vol. 19, No. 22, 15.11.2013, p. 6219-6229.

Research output: Contribution to journalArticle

Flanigan, SA, Pitts, TM, Newton, TP, Kulikowski, GN, Tan, A-C, McManus, MC, Spreafico, A, Kachaeva, MI, Selby, HM, Tentler, JJ, Eckhardt, SG & Leong, S 2013, 'Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models', Clinical Cancer Research, vol. 19, no. 22, pp. 6219-6229. https://doi.org/10.1158/1078-0432.CCR-13-0145
Flanigan SA, Pitts TM, Newton TP, Kulikowski GN, Tan A-C, McManus MC et al. Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models. Clinical Cancer Research. 2013 Nov 15;19(22):6219-6229. https://doi.org/10.1158/1078-0432.CCR-13-0145
Flanigan, Sara A. ; Pitts, Todd M. ; Newton, Timothy P. ; Kulikowski, Gillian N. ; Tan, Aik-Choon ; McManus, Martine C. ; Spreafico, Anna ; Kachaeva, Maria I. ; Selby, Heather M. ; Tentler, John J. ; Eckhardt, S. Gail ; Leong, Stephen. / Overcoming IGF1R/IR resistance through inhibition of MEK signaling in colorectal cancer models. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 22. pp. 6219-6229.
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