Tumor Biology

, Volume 36, Issue 4, pp 2993–2999 | Cite as

Acquired resistance to EGFR tyrosine kinase inhibitor in A431 squamous cell carcinoma xenografts is mediated by c-Kit pathway transduction

  • Lixia Zhang
  • Xiaokun Yang
  • Bei Zhao
  • Zhen Cai
Research Article


Epidermal growth factor inhibitors (EGFRIs), the first targeted cancer therapy, are currently an essential treatment for many advance-stage epithelial cancers. These agents have the superior ability to target cancers cells and better safety profile compared to conventional chemotherapies. However, all responding patients eventually developed acquired resistance to EGFRIs and the mechanisms of acquired resistance invariably develops. In the current study, we reported the tumor xenografts of the human A431 squamous cell carcinoma, after 25-week consecutive therapy with EGFR inhibitor (gefitinib) that developed resistance as a result of c-Kit overexpression. Moreover, combined therapeutic inhibition of EGFR and c-Kit may abrogate this acquired mechanism of drug resistance due to an enhanced apoptotic effect in gefitinib-resistant xenograft model. Taken together, the results suggest that at least in the A431 xenograft model displaying acquired resistance to gefitinib can emerge in vivo, at least in part, by mechanisms involving the c-Kit overexpression.


EGFR A431 c-Kit Squamous cell carcinoma 



The authors thank Shang Wu for bioinformatics analysis of the Gene Chip of SNP 6.0 and U133 plus 2.0 arrays’ data.

Conflicts of interest



  1. 1.
    Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. N Engl J Med. 2008;358:1160–74.CrossRefPubMedGoogle Scholar
  2. 2.
    Harari PM, Allen GW, Bonner JA. Biology of interactions: Antiepidermal growth factor receptor agents. J Clin Oncol. 2007;25:4057–65.CrossRefPubMedGoogle Scholar
  3. 3.
    Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, et al. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, et al. Met amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A. 2007;104:20932–7.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039–43.CrossRefPubMedGoogle Scholar
  6. 6.
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, Fidias P, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med. 2011;3:75ra26.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Pao W, Wang TY, Riely GJ, Miller VA, Pan Q, Ladanyi M, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:e17.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cappuzzo F, Hirsch FR, Rossi E, Bartolini S, Ceresoli GL, Bemis L, et al. Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non–small-cell lung cancer. J Natl Cancer Inst. 2005;97:643–55.CrossRefPubMedGoogle Scholar
  9. 9.
    Tsao MS, Sakurada A, Cutz JC, Zhu CQ, Kamel-Reid S, Squire J, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Engl J Med. 2005;353:133–44.CrossRefPubMedGoogle Scholar
  10. 10.
    Koike C, Mizutani T, Ito T, Shimizu Y, Yamamichi N, Kameda T, et al. Introduction of wild-type patched gene suppresses the oncogenic potential of human squamous cell carcinoma cell lines including A431. Oncogene. 2002;21:2670–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Polverino A, Coxon A, Starnes C, Diaz Z, DeMelfi T, Wang L, et al. AMG 706, an oral, multikinase inhibitor that selectively targets vascular endothelial growth factor, platelet-derived growth factor, and kit receptors, potently inhibits angiogenesis and induces regression in tumor xenografts. Cancer Res. 2006;66:8715–21.CrossRefPubMedGoogle Scholar
  12. 12.
    Ulivi P, Zoli W, Capelli L, Chiadini E, Calistri D, Amadori D. Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation. Mol Clin Oncol. 2013;1:575–81.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Takeda M, Okamoto I, Nakagawa K. Survival outcome assessed according to tumor response and shrinkage pattern in patients with EGFR mutation-positive non-small-cell lung cancer treated with gefitinib or erlotinib. J Thorac Oncol. 2014;9:200–4.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Engelman JA, Luo J, Cantley LC. The evolution of phosphatidylinositol3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006;7:606–19.CrossRefPubMedGoogle Scholar
  15. 15.
    Bianco R, Shin I, Ritter CA, Yakes FM, Basso A, Rosen N, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003;22:2812–22.CrossRefPubMedGoogle Scholar
  16. 16.
    Mellinghoff IK, Wang MY, Vivanco I, Haas-Kogan DA, Zhu S, Dia EQ, et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N Engl J Med. 2005;353:2012–24.CrossRefPubMedGoogle Scholar
  17. 17.
    Yuan TL, Cantley LC. PI3K pathway alterations in cancer: Variations on a theme. Oncogene. 2008;27:5497–510.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Engelman JA, Mukohara T, Zejnullahu K, Lifshits E, Borrás AM, Gale CM, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Investig. 2006;116:2695–706.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  1. 1.Department of Dermatology and VenereologySichuan Academy of Medical Sciences and Sichuan Provincial People’s HospitalChengduChina
  2. 2.Department of EmergencyChengdu Military General HospitalChengduChina
  3. 3.Department of Plastic SurgerySichuan Academy of Medical Sciences and Sichuan Provincial People’s HospitalChengduChina

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