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Schulz D, Wirth M, Piontek G, et al. HNSCC cells resistant to EGFR pathway inhibitors are hypermutated and sensitive to DNA damaging substances. Am J Cancer Res. 2016;6(9):1963-1975
Schulz, D., Wirth, M., Piontek, G., Buchberger, A. M., Schlegel, J., Reiter, R., Multhoff, G., & Pickhard, A. (2016). HNSCC cells resistant to EGFR pathway inhibitors are hypermutated and sensitive to DNA damaging substances. American journal of cancer research, 6(9), 1963-1975.
Schulz, Dominik, et al. "HNSCC cells resistant to EGFR pathway inhibitors are hypermutated and sensitive to DNA damaging substances." American journal of cancer research vol. 6,9 (2016): 1963-1975.
Schulz D, Wirth M, Piontek G, Buchberger AM, Schlegel J, Reiter R, Multhoff G, Pickhard A. HNSCC cells resistant to EGFR pathway inhibitors are hypermutated and sensitive to DNA damaging substances. Am J Cancer Res. 2016 Sep 01;6(9):1963-1975. eCollection 2016. PMID: 27725902; PMCID: PMC5043106.
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Am J Cancer Res. 2016 Sep 01;6(9):1963-1975. eCollection 2016.

HNSCC cells resistant to EGFR pathway inhibitors are hypermutated and sensitive to DNA damaging substances.

American journal of cancer research

Dominik Schulz, Markus Wirth, Guido Piontek, Anna Maria Stefanie Buchberger, Jürgen Schlegel, Rudolf Reiter, Gabriele Multhoff, Anja Pickhard

Affiliations

  1. Department of Otolaryngology Head and Neck Surgery, Technical University of Munich Ismaninger Straße 22, Munich, Germany.
  2. Division of Neuropathology, Institute of Pathology, Technical University of Munich Ismaninger Straße 22, Munich, Germany.
  3. Department of Otolaryngology Head and Neck Surgery, Section of Phoniatrics and Pedaudiology, University of Ulm Prittwitzstraße 43, Ulm, Germany.
  4. Department of Radiotherapy, Technical University of Munich Ismaninger Straße 22, Munich, Germany.

PMID: 27725902 PMCID: PMC5043106

Abstract

Despite remarkable successes with targeted therapies in the treatment of cancer, resistance can occur which limits the clinical outcome. In this study, we generated and characterized resistant cell clones derived from two different head and neck squamous cell carcinoma (HNSCC) cell lines (Cal27, UD-SCC-5) by long-term exposure to five targeted- and chemotherapeutics (afatinib, MK2206, BEZ235, olaparib and cisplatin). The resistant tumor cell clones showed an increased ERK1/2 expression and an altered expression of the stem-cell markers CD44, ALDH1, Oct4, Sox2, Nanog and Bmi1. None of the single markers alone was predictive for resistance to all five targeted- and chemotherapeutics. Furthermore, long-term exposure of tumor cells to these five drugs resulted in an eightfold increase in the mutational rate compared to untreated cells. Interestingly, targeted- and chemotherapy resistant cell clones remained sensitive to irradiation. Lastly, clones that were resistant to afatinib, MK2206 or BEZ235 showed cross-resistance to further treatment with therapeutics that affect the same signaling pathway, but remained sensitive to those affecting different pathways such as cisplatin and olaparib. In contrast, cell clones which were once resistant to cisplatin or olaparib were found to be multidrug-resistant. These data might indicate that patients with HNSCC benefit more by a first line targeted therapy followed by cisplatin as a second line therapy.

Keywords: HNSCC; hypermutation; resistant cells

References

  1. Cell. 2009 Aug 7;138(3):592-603 - PubMed
  2. N Engl J Med. 2015 Apr 30;372(18):1700-9 - PubMed
  3. Nucleic Acids Res. 2011 Jun;39(11):e73 - PubMed
  4. Mol Cancer Ther. 2012 Mar;11(3):784-91 - PubMed
  5. Cancer Prev Res (Phila). 2011 Mar;4(3):454-62 - PubMed
  6. PLoS One. 2008 Jun 18;3(6):e2428 - PubMed
  7. Am J Clin Oncol. 2003 Aug;26(4):e73-9 - PubMed
  8. PLoS One. 2013;8(2):e56324 - PubMed
  9. J Clin Pharmacol. 2005 Aug;45(8):872-7 - PubMed
  10. Nat Rev Cancer. 2005 Apr;5(4):275-84 - PubMed
  11. Cancer Control. 2003 Mar-Apr;10(2):159-65 - PubMed
  12. J Cell Biol. 2012 Aug 6;198(3):281-93 - PubMed
  13. Nat Med. 2011 Mar;17(3):313-9 - PubMed
  14. Int J Cancer. 2003 Aug 10;106(1):66-73 - PubMed
  15. Clin Cancer Res. 2006 Oct 1;12(19):5764-9 - PubMed
  16. Nat Rev Cancer. 2011 Jan;11(1):9-22 - PubMed
  17. Cell Stem Cell. 2007 Sep 13;1(3):313-23 - PubMed
  18. Cancer Chemother Pharmacol. 2002 Nov;50(5):397-404 - PubMed
  19. Blood. 2008 Sep 15;112(6):2489-99 - PubMed
  20. Tumour Biol. 2012 Jun;33(3):707-21 - PubMed
  21. J Exp Clin Cancer Res. 2009 Jun 02;28:72 - PubMed
  22. Histochemie. 1966;7(3):273-87 - PubMed
  23. Nat Genet. 2006 Apr;38(4):431-40 - PubMed
  24. Cancer Treat Rev. 2012 Oct;38(6):589-98 - PubMed
  25. N Engl J Med. 2005 Feb 24;352(8):786-92 - PubMed
  26. Proc Natl Acad Sci U S A. 2007 Jan 16;104(3):973-8 - PubMed
  27. Nat Rev Cancer. 2013 Oct;13(10):714-26 - PubMed
  28. Cancer Res. 2007 Dec 15;67(24):11933-41 - PubMed
  29. Histopathology. 2011 Oct;59(4):763-75 - PubMed
  30. Lancet Oncol. 2012 Apr;13(4):e178-85 - PubMed
  31. N Engl J Med. 2015 Apr 30;372(18):1689-99 - PubMed
  32. CA Cancer J Clin. 2013 Jan;63(1):11-30 - PubMed
  33. Oncogene. 2013 Feb 28;32(9):1173-82 - PubMed
  34. Blood. 2010 Nov 25;116(22):4578-87 - PubMed
  35. Oncogene. 2008 Jun 26;27(28):3944-56 - PubMed
  36. Head Neck. 2010 Sep;32(9):1195-201 - PubMed
  37. Onco Targets Ther. 2012;5:127-31 - PubMed
  38. Nature. 2003 May 15;423(6937):302-5 - PubMed
  39. Nature. 2012 Jun 28;486(7404):532-6 - PubMed
  40. Nature. 2006 Dec 7;444(7120):756-60 - PubMed
  41. Genome Res. 2013 Sep;23(9):1434-45 - PubMed
  42. N Engl J Med. 2004 May 6;350(19):1945-52 - PubMed
  43. Ann Oncol. 2010 Oct;21 Suppl 7:vii252-61 - PubMed
  44. Cancer Cell. 2010 Dec 14;18(6):683-95 - PubMed
  45. Radiother Oncol. 1996 Apr;39(1):81-6 - PubMed
  46. Br J Cancer. 2014 Apr 15;110(8):2063-71 - PubMed
  47. Nature. 2010 Dec 16;468(7326):973-7 - PubMed
  48. Clin Cancer Res. 2014 Jun 1;20(11):2933-46 - PubMed

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