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. 2019 Dec 9;19(9):1605–1612. doi: 10.1093/annonc/mdn240

Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors

PA Zucali 1, MG Ruiz 2, E Giovannetti 2, A Destro 3, M Varella-Garcia 4, K Floor 2, GL Ceresoli 1, JA Rodriguez 2, I Garassino 1, P Comoglio 5, M Roncalli 3, A Santoro 1, G Giaccone 2,*
PMCID: PMC7360138  PMID: 18467317

Abstract

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.

Keywords: activated cMET, gefitinib resistance, multitarget therapy, NSCLC

Full Text

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references

  • 1.Pao W., Miller V.A., Politi K.A. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2:e73. doi: 10.1371/journal.pmed.0020073. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Kobayashi S., Boggon T.J., Dayaram T. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352:786–792. doi: 10.1056/NEJMoa044238. [DOI] [PubMed] [Google Scholar]
  • 3.Mitsudomi T., Kosaka T., Yatabe Y. Biological and clinical implications of EGFR mutations in lung cancer. Int J Clin Oncol. 2006;11:190–198. doi: 10.1007/s10147-006-0583-4. [DOI] [PubMed] [Google Scholar]
  • 4.Pao W., Wang T.Y., Riely G.J. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:e17. doi: 10.1371/journal.pmed.0020017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Giaccone G., Gallegos Ruiz M., Le Chevalier T. Erlotinib for frontline treatment of advanced non-small cell lung cancer: a phase II study. Clin Cancer Res. 2006;12:6049–6055. doi: 10.1158/1078-0432.CCR-06-0260. [DOI] [PubMed] [Google Scholar]
  • 6.Janmaat M.L., Kruyt F.A., Rodriguez J.A., Giaccone G. Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res. 2003;9:2316–2326. [PubMed] [Google Scholar]
  • 7.She Q.B., Solit D., Basso A., Moasser M.M. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3′-kinase/Akt pathway signaling. Clin Cancer Res. 2003;9:4340–4346. [PubMed] [Google Scholar]
  • 8.Qin B., Ariyama H., Baba E. Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream of epidermal growth factor receptor in human gallbladder adenocarcinoma cells. Cancer Chemother Pharmacol. 2006;58:577–584. doi: 10.1007/s00280-006-0219-4. [DOI] [PubMed] [Google Scholar]
  • 9.Thiery J.P. Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454. doi: 10.1038/nrc822. [DOI] [PubMed] [Google Scholar]
  • 10.Witta S.E., Gemmill R.M., Hirsch F.R. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res. 2006;66:944–950. doi: 10.1158/0008-5472.CAN-05-1988. [DOI] [PubMed] [Google Scholar]
  • 11.Yauch R.L., Januario T., Eberhard D.A. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res. 2005;11:8686–8698. doi: 10.1158/1078-0432.CCR-05-1492. [DOI] [PubMed] [Google Scholar]
  • 12.Natali P.G., Prat M., Nicotra M.R. Overexpression of the met/HGF receptor in renal cell carcinomas. Int J Cancer. 1996;69:212–217. doi: 10.1002/(SICI)1097-0215(19960621)69:3<212::AID-IJC11>3.0.CO;2-9. [DOI] [PubMed] [Google Scholar]
  • 13.Olivero M., Rizzo M., Madeddu R. Overexpression and activation of hepatocyte growth factor/scatter factor in human non-small-cell lung carcinomas. Br J Cancer. 1996;74:1862–1868. doi: 10.1038/bjc.1996.646. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Maulik G., Kijima T., Ma P.C. Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer. Clin Cancer Res. 2002;8:620–627. [PubMed] [Google Scholar]
  • 15.Ma P.C., Jagadeeswaran R., Jagadeesh S. Functional expression and mutations of c-Met and its therapeutic inhibition with SU11274 and small interfering RNA in non-small cell lung cancer. Cancer Res. 2005;65:1479–1488. doi: 10.1158/0008-5472.CAN-04-2650. [DOI] [PubMed] [Google Scholar]
  • 16.Mazzone M., Comoglio P.M. The Met pathway: master switch and drug target in cancer progression. FASEB J. 2006;20:1611–1621. doi: 10.1096/fj.06-5947rev. [DOI] [PubMed] [Google Scholar]
  • 17.Siegfried J.M., Weissfeld L.A., Luketich J.D. The clinical significance of hepatocyte growth factor for non-small cell lung cancer. Ann Thorac Surg. 1998;66:1915–1918. doi: 10.1016/s0003-4975(98)01165-5. [DOI] [PubMed] [Google Scholar]
  • 18.Petrelli A., Circosta P., Granziero L. Antibody-induced ectodomain shedding mediates HGF receptor down-regulation and hampers biological activity. Proc Natl Acad Sci USA. 2006;103:5090–5095. doi: 10.1073/pnas.0508156103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Engelman J.A., Zejnullahu K., Mitsudomi T. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–1043. doi: 10.1126/science.1141478. [DOI] [PubMed] [Google Scholar]
  • 20.Therasse P. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205–216. doi: 10.1093/jnci/92.3.205. [DOI] [PubMed] [Google Scholar]
  • 21.Meier R., Alessi D.R., Cron P. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem. 1997;272:30491–30497. doi: 10.1074/jbc.272.48.30491. [DOI] [PubMed] [Google Scholar]
  • 22.Cappuzzo F., Magrini E., Ceresoli G.L. Akt phosphorylation and gefitinib efficacy in patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 2004;96:1133–1141. doi: 10.1093/jnci/djh217. [DOI] [PubMed] [Google Scholar]
  • 23.Janmaat M.L., Rodriguez J.A., Gallegos-Ruiz M. Enhanced cytotoxicity induced by gefitinib and specific inhibitors of the Ras or phosphatidyl inositol-3 kinase pathways in non-small cell lung cancer cells. Int J Cancer. 2006;118:209–214. doi: 10.1002/ijc.21290. [DOI] [PubMed] [Google Scholar]
  • 24.Prat M., Crepaldi T., Pennacchietti S. Agonistic monoclonal antibodies against the Met receptor dissect the biological responses to HGF. J Cell Sci. 1998;111:237–247. doi: 10.1242/jcs.111.2.237. [DOI] [PubMed] [Google Scholar]
  • 25.Chou T.C., Motzer R.J., Tong Y., Bosl G.J. Computerized quantitation of synergism and antagonism of taxol, topotecan, and cisplatin against human teratocarcinoma cell growth: a rational approach to clinical protocol design. J Natl Cancer Inst. 1994;86:1517–1524. doi: 10.1093/jnci/86.20.1517. [DOI] [PubMed] [Google Scholar]
  • 26.Lutterbach B., Zeng Q., Davis L.J. Lung cancer cell lines harboring MET gene amplification are dependent on Met for growth and survival. Cancer Res. 2007;67:2081–2088. doi: 10.1158/0008-5472.CAN-06-3495. [DOI] [PubMed] [Google Scholar]

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