Annals of Oncology Advance Access originally published online on May 7, 2008
Annals of Oncology 2008 19(9):1605-1612; doi:10.1093/annonc/mdn240
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lung cancer |
Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors
1 Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Milan, Italy
2 Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
3 Department of Human Pathology, Istituto Clinico Humanitas, Rozzano, Milan and University of Milan Medical School, Milan, Italy
4 Department of Medicine/Medical Oncology, University of Colorado Cancer Center, Aurora, CO, USA
5 Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Turin, Italy
* Correspondence to: Dr G. Giaccone, Clinical Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive Building 10, Room 12 N226, Bethesda, MD 20892-1906, USA. Tel: +1-301-4023415; Fax: +1-301-4020172; E-mail: giacconeg{at}mail.nih.gov
Background: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC.
Materials and methods: pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells.
Results: EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied.
Conclusions: Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC.
Key words: activated cMET, gefitinib resistance, multitarget therapy, NSCLC
Received for publication January 23, 2008. Revision received March 28, 2008. Accepted for publication April 7, 2008.
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