ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer

Rebekah L. Zinn, Eric E. Gardner, Luigi Marchionni, Sara C. Murphy, Irina Dobromilskaya, Christine Hann, Charles M. Rudin

Research output: Contribution to journalArticle

Abstract

New therapies are critically needed to improve the outcome for patients with small cell lung cancer (SCLC). Insulin-like growth factor 1 receptor (IGF-1R) inhibition is a potential treatment strategy for SCLC: the IGF-1R pathway is commonly upregulated in SCLC and has been associated with inhibition of apoptosis and stimulation of proliferation through downstream signaling pathways, including phospha-tidylinositol-3-kinase-Akt and mitogen-activated protein kinase. To evaluate potential determinants of response to IGF-1R inhibition, we assessed the relative sensitivity of 19 SCLC cell lines to OSI-906, a small molecule inhibitor of IGF-1R, and the closely related insulin receptor. Approximately one third of these cell lines were sensitive to OSI-906, with an IC50 <1 μmol/L. Cell line expression of IGF-1R, IR, IGF-1, IGF-2, IGFBP3, and IGFBP6 did not correlate with sensitivity to OSI-906. Interestingly, OSI-906 sensitive lines expressed significantly lower levels of baseline phospho-ERK relative to resistant lines (P = 0.006). OSI-906 treatment resulted in dose-dependent inhibition of phospho-IGF-1R and phospho-Akt in both sensitive and resistant cell lines, but induced apoptosis and cell-cycle arrest only in sensitive lines. We tested the in vivo efficacy of OSI-906 using an NCI-H187 xenograft model and two SCLC patient xenografts in mice. OSI-906 treatment resulted in 50% tumor growth inhibition in NCI-H187 and 30% inhibition in the primary patient xenograft models compared with mock-treated animals. Taken together our data support IGF-1R inhibition as a viable treatment strategy for a defined subset of SCLC and suggest that low pretreatment levels of phospho-ERK may be indicative of sensitivity to this therapeutic approach.

Original languageEnglish (US)
Pages (from-to)1131-1139
Number of pages9
JournalMolecular Cancer Therapeutics
Volume12
Issue number6
DOIs
StatePublished - Jun 2013

Fingerprint

Somatomedin Receptors
Small Cell Lung Carcinoma
Phosphorylation
Heterografts
Cell Line
Therapeutics
MAP Kinase Kinase 3
Apoptosis
Insulin-Like Growth Factor II
Insulin Receptor
Cell Cycle Checkpoints
3-(8-amino-1-(2-phenylquinolin-7-yl)imidazo(1,5-a)pyrazin-3-yl)-1-methylcyclobutanol
Insulin-Like Growth Factor I
Inhibitory Concentration 50
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer. / Zinn, Rebekah L.; Gardner, Eric E.; Marchionni, Luigi; Murphy, Sara C.; Dobromilskaya, Irina; Hann, Christine; Rudin, Charles M.

In: Molecular Cancer Therapeutics, Vol. 12, No. 6, 06.2013, p. 1131-1139.

Research output: Contribution to journalArticle

Zinn, Rebekah L. ; Gardner, Eric E. ; Marchionni, Luigi ; Murphy, Sara C. ; Dobromilskaya, Irina ; Hann, Christine ; Rudin, Charles M. / ERK phosphorylation is predictive of resistance to IGF-1R inhibition in small cell lung cancer. In: Molecular Cancer Therapeutics. 2013 ; Vol. 12, No. 6. pp. 1131-1139.
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