Abstract 4127: EGFR and K-Ras mutations and resistance of lung cancer to the IGF-1R tyrosine kinase inhibitors

Abstract

Abstract Background: The majority of patients with non-small cell lung cancer (NSCLC) has responded poorly to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We investigated (1) the involvement of insulin-like growth factor 1 receptor (IGF-1R) signaling in primary resistance to EGFR TKIs and (2) the molecular determinants of resistance to IGF-1R TKIs. Methods: Phosphorylated IGF-1R/insulin receptor (pIGF-1R/IR) was immunohistochemically evaluated in NSCLC tissue microarrays. The antitumor effects of IGF-1R TKIs (PQIP, OSI906), either alone or in combination with small-molecular inhibitors or siRNA targeting K-Ras or MAPK/extracellular signal-regulated kinase kinase (MEK) were analyzed in vitro and in vivo in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-transformed human bronchial epithelial (HBE) cells and in NSCLC cells with variable histologic features and mutations in EGFR or K-Ras. Results: pIGF-1R/IR expression in NSCLC specimens was positively correlated with presence of a history of tobacco smoking, squamous cell carcinoma, mutant (mut) 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 NNK-transformed HBE cells and in NSCLC cells harboring wt EGFR and wt K-Ras, but not those with mutations in these genes. Introduction of mut K-Ras attenuated the effects of IGF-1R TKIs on wt K-Ras-expressing NSCLC cells. Conversely, inactivation of MEK restored sensitivity to IGFR-TKI in cells carrying mut K-Ras. Conclusions: The mutation status of both EGFR and K-Ras could be a predictive marker for response to IGF-1R TKIs. Also, MEK antagonism can abrogate primary resistance of NSCLC to IGF-1R TKIs. This work was supported by NIH grants R01 CA-109520-01 and CA-100816 (all to H-YL.) and in part by DOD grant W81XWH-04-1-0142 VITAL and W8XWH-06-1-0303 BATTLE (W-K H.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4127.