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Epidermal growth factor receptor and K‐Ras mutations and resistance of lung cancer to insulin‐like growth factor 1 receptor tyrosine kinase inhibitors
Author(s) -
Kim WooYoung,
Prudkin Ludmila,
Feng Lei,
Kim Edward S.,
Hennessy Bryan,
Lee JuSeog,
Lee J. Jack,
Glisson Bonnie,
Lippman Scott M.,
Wistuba Ignacio I.,
Hong Waun Ki,
Lee HoYoung
Publication year - 2012
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.26656
Subject(s) - epidermal growth factor receptor , cancer research , erlotinib , tyrosine kinase , growth factor receptor , medicine , lung cancer , growth factor receptor inhibitor , epidermal growth factor , cancer , biology , receptor
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.