Epidermal growth factor receptor and K‐Ras mutations and resistance of lung cancer to insulin‐like growth factor 1 receptor tyrosine kinase inhibitors

• Published in: Cancer 2012-08, Vol.118 (16), p.3993-4003
• Main Authors: Kim, Woo‐Young, Prudkin, Ludmila, Feng, Lei, Kim, Edward S., Hennessy, Bryan, Lee, Ju‐Seog, Lee, J. Jack, Glisson, Bonnie, Lippman, Scott M., Wistuba, Ignacio I., Hong, Waun Ki, Lee, Ho‐Young
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Drug Resistance, Neoplasm - genetics; epidermal growth factor receptor; Extracellular Signal-Regulated MAP Kinases - metabolism; Genes, ras; Humans; insulinlike growth factor 1 receptor; K‐Ras; lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical sciences; Mice; Mice, Nude; Mutation; Pneumology; Protein Kinase Inhibitors - therapeutic use; Receptor, Epidermal Growth Factor - genetics; Receptor, IGF Type 1 - antagonists & inhibitors; Smoking - adverse effects; Tumors; Tumors of the respiratory system and mediastinum; tyrosine kinase inhibitors; Xenograft Model Antitumor Assays
• ISSN: 0008-543X; 1097-0142
• DOI: 10.1002/cncr.26656

BACKGROUND: Most patients with nonsmall cell lung cancer (NSCLC) have responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The authors investigated the involvement of insulinlike growth factor 1 receptor (IGF‐1R) signaling in primary resistance to EGFR TKIs and the molecular determinants of resistance to IGF‐1R TKIs. METHODS: Phosphorylated IGF‐1R/insulin receptor (pIGF‐1R/IR) was immunohistochemically evaluated in an NSCLC tissue microarray. The authors analyzed the antitumor effects of an IGF‐1R TKI (PQIP or OSI‐906), either alone or in combination with a small‐molecular inhibitor (PD98059 or U0126) or with siRNA targeting K‐Ras or mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase (MEK), in vitro and in vivo in NSCLC cells with variable histologic features and EGFR or K‐Ras mutations. RESULTS: pIGF‐1R/IR expression in NSCLC specimens was associated with a history of tobacco smoking, squamous cell carcinoma histology, mutant K‐Ras, and wild‐type (WT) EGFR, all of which have been strongly associated with poor response to EGFR TKIs. IGF‐1R TKIs exhibited significant antitumor activity in NSCLC cells with WT EGFR and WT K‐Ras but not in those with mutations in these genes. Introduction of mutant K‐Ras attenuated the effects of IGF‐1R TKIs on NSCLC cells expressing WT K‐Ras. Conversely, inactivation of MEK restored sensitivity to IGF‐TKIs in cells carrying mutant K‐Ras. CONCLUSIONS: The mutation status of both EGFR and K‐Ras could be a predictive marker of response to IGF‐1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC cells to IGF‐1R TKIs. Cancer 2012. © 2012 American Cancer Society. This study provides evidence for the first time that the mutation status of both epidermal growth factor receptor (EGFR) and K‐Ras could be a predictive marker for response to insulinlike growth factor 1 receptor (IGF‐1R) tyrosine kinase inhibitors (TKIs). Also, mitogen‐activated protein kinase/extracellular signal‐regulated kinase kinase antagonism can abrogate primary resistance of nonsmall cell lung cancer to IGF‐1R TKIs.