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Dacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro

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Tumor Biology

Abstract

Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer that carries an extremely poor prognosis. Up to 35 % of USC may overexpress the epidermal growth factor receptor-2 (HER2/neu) at strong (i.e., 3+) level by immunohistochemistry (IHC) or harbor HER2/neu gene amplification by fluorescence in situ hybridization (FISH). In this study, we assessed the sensitivity of a panel of USC cell lines with and without HER2/neu gene amplification to dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor tyrosine kinase inhibitor. Eight primary cell lines (i.e., four harboring HER2/neu gene amplification by FISH and four FISH− cell lines), all demonstrating similar in vitro growth rates, were evaluated in viability/proliferation assays. The effect of dacomitinib on cell growth, cell cycle distribution, and signaling was determined using flow cytometry-based assays. Dacomitinib caused a significantly stronger growth inhibition in HER2/neu FISH+ USC cell lines when compared to FISH− USC (dacomitinib half maximal inhibitory concentration (IC50) mean ± SEM = 0.02803 ± 0.003355 μM in FISH+ versus 1.498 ± 0.2209 μM in FISH− tumors, P < 0.0001). Dacomitinib growth inhibition was associated with a significant and dose-dependent decline in phosphorylated HER2/neu and S6 transcription factor and a dose-dependent and time-dependent cell cycle arrest in G0/G1 in FISH+ USC. Dacomitinib is remarkably effective against chemotherapy-resistant HER2/neu gene-amplified USC. Clinical studies with dacomitinib in HER2/neu FISH+ USC patients resistant to standard salvage chemotherapy are warranted.

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References

  1. Hendrickson M, Ross J, Eifel P, Martinez A, Kempson R. Uterine papillary serous carcinoma: a highly malignant form of endometrial adenocarcinoma. Am J Surg Pathol. 1982;6:93–108.

    Article  CAS  PubMed  Google Scholar 

  2. Hamilton CA, Cheung MK, Osann K, Chen L, Teng NN, Longacre TA. Uterine papillary serous and clear cell carcinomas predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer. 2006;94:642–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Boruta 2nd DM, Gehrig PA, Groben PA, Bae-Jump V, Boggess JF, Fowler Jr WC, et al. Uterine serous and grade 3 endometrioid carcinomas: is there a survival difference? Cancer. 2004;101:2214–21.

    Article  PubMed  Google Scholar 

  4. Acharya S, Hensley ML, Montag AC, Fleming GF. Rare uterine cancers. Lancet Oncol. 2005;6:961–71.

    Article  PubMed  Google Scholar 

  5. del Carmen MG, Birrer M, Schorge JO. Uterine papillary serous cancer: a review of the literature. Gynecol Oncol. 2012;127:651–61.

    Article  PubMed  Google Scholar 

  6. Goff BA. Uterine papillary serous carcinoma: what have we learned over the past quarter century? Gynecol Oncol. 2005;98:341–3.

    Article  PubMed  Google Scholar 

  7. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.

    Article  CAS  PubMed  Google Scholar 

  8. Grushko TA, Filiaci VL, Mundt AJ, Ridderstrale K, Olopade OI, Fleming GF, et al. An exploratory analysis of HER-2 amplification and overexpression in advanced endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol. 2008;108:3–9.

    Article  CAS  PubMed  Google Scholar 

  9. English DP, Roque DM, Santin AD. HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol Diagn Ther. 2013;17:85–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127–37.

    Article  CAS  PubMed  Google Scholar 

  11. Kim SM, Kwon OJ, Hong YK, Kim JH, Solca F, Ha SJ, et al. Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation. Mol Cancer Ther. 2012;11:2254–64.

    Article  CAS  PubMed  Google Scholar 

  12. Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet: Off Organ Int Fed Gynaecol Obstet. 2009;105:107–8.

    Article  Google Scholar 

  13. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353:1659–72.

    Article  CAS  PubMed  Google Scholar 

  14. Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380–8.

    Article  CAS  PubMed  Google Scholar 

  15. Gonzales AJ, Hook KE, Althaus IW, Ellis PA, Trachet E, Delaney AM, et al. Antitumor activity and pharmacokinetic properties of PF-00299804, a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor. Mol Cancer Ther. 2008;7:1880–9.

    Article  CAS  PubMed  Google Scholar 

  16. English DP, Bellone S, Cocco E, Bortolomai I, Pecorelli S, Lopez S, et al. Oncogenic PIK3CA gene mutations and HER2/neu gene amplifications determine the sensitivity of uterine serous carcinoma cell lines to GDC-0980, a selective inhibitor of Class I Pi3 kinase and mTOR kinase (TORC1/2). Am J Obstet Gynecol. 2013;209:465 e461–469.

    Article  Google Scholar 

  17. Schwab CL, Bellone S, English DP, Roque DM, Lopez S, Cocco E, et al. Afatinib demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro and in vivo. Br J Cancer. 2014;111(9):1750–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhao S, Choi M, Overton JD, Bellone S, Roque DM, Cocco E, et al. Landscape of somatic single-nucleotide and copy-number mutations in uterine serous carcinoma. Proc Natl Acad Sci U S A. 2013;110:2916–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Reckamp KL, Giaccone G, Camidge DR, Gadgeel SM, Khuri FR, Engelman JA, et al. A phase 2 trial of dacomitinib (PF-00299804), an oral, irreversible pan-HER (human epidermal growth factor receptor) inhibitor, in patients with advanced non-small cell lung cancer after failure of prior chemotherapy and erlotinib. Cancer. 2014;120:1145–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ramalingam SS, Blackhall F, Krzakowski M, Barrios CH, Park K, Bover I, et al. Randomized phase II study of dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor inhibitor, versus erlotinib in patients with advanced non-small-cell lung cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2012;30:3337–44.

    Article  CAS  Google Scholar 

  21. Janne PA, Boss DS, Camidge DR, Britten CD, Engelman JA, Garon EB, et al. Phase I dose-escalation study of the pan-HER inhibitor, PF299804, in patients with advanced malignant solid tumors. Clin Cancer Res: Off J Am Assoc Cancer Res. 2011;17:1131–9.

    Article  CAS  Google Scholar 

  22. Cancer Genome Atlas Research N, Kandoth C, Schultz N, Cherniack AD, Akbani R, Liu Y, et al. Integrated genomic characterization of endometrial carcinoma. Nature. 2013;497:67–73.

    Article  Google Scholar 

  23. Wright C, Angus B, Nicholson S, Sainsbury JR, Cairns J, Gullick WJ, et al. Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast cancer. Cancer Res. 1989;49:2087–90.

    CAS  PubMed  Google Scholar 

  24. Berchuck A, Kamel A, Whitaker R, Kerns B, Olt G, Kinney R, et al. Overexpression of HER-2/neu is associated with poor survival in advanced epithelial ovarian cancer. Cancer Res. 1990;50:4087–91.

    CAS  PubMed  Google Scholar 

  25. Hetzel DJ, Wilson TO, Keeney GL, Roche PC, Cha SS, Podratz KC. Her-2/neu expression: a major prognostic factor in endometrial cancer. Gynecol Oncol. 1992;47:179–85.

    Article  CAS  PubMed  Google Scholar 

  26. Tanner M, Hollmen M, Junttila TT, Kapanen AI, Tommola S, Soini Y, et al. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol: Off J Eur Soc Med Oncol / ESMO. 2005;16:273–8.

    Article  CAS  Google Scholar 

  27. Santin AD, Bellone S, Gokden M, Palmieri M, Dunn D, Agha J, et al. Overexpression of HER-2/neu in uterine serous papillary cancer. Clin Cancer Res: Off J Am Assoc Cancer Res. 2002;8:1271–9.

    CAS  Google Scholar 

  28. Fleming GF, Sill MW, Darcy KM, McMeekin DS, Thigpen JT, Adler LM, et al. Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a gynecologic oncology group study. Gynecol Oncol. 2010;116:15–20.

    Article  CAS  PubMed  Google Scholar 

  29. Villella JA, Cohen S, Smith DH, Hibshoosh H, Hershman D. Her-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc. 2006;16:1897–902.

    Article  CAS  Google Scholar 

  30. Jewell E, Secord AA, Brotherton T, Berchuck A. Use of trastuzumab in the treatment of metastatic endometrial cancer. Int J Gynecol Cancer: Off J Int Gynecol Cancer Soc. 2006;16:1370–3.

    Article  CAS  Google Scholar 

  31. Santin AD, Bellone S, Roman JJ, McKenney JK, Pecorelli S. Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet: Off Organ Int Fed Gynaecol Obstet. 2008;102:128–31.

    Article  CAS  Google Scholar 

  32. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, et al. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99:628–38.

    Article  CAS  PubMed  Google Scholar 

  33. Todeschini P, Cocco E, Bellone S, Varughese J, Lin K, Carrara L, et al. Her2/neu extracellular domain shedding in uterine serous carcinoma: implications for immunotherapy with trastuzumab. Br J Cancer. 2011;105:1176–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wissner A, Overbeek E, Reich M, Floyd MB, Johnson B, Mamuya N, et al. Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem. 2003;46:49–63.

    Article  CAS  PubMed  Google Scholar 

  35. Tsou HR, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD, et al. Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem. 2005;48:1107–31.

    Article  CAS  PubMed  Google Scholar 

  36. Kalous O, Conklin D, Desai AJ, O’Brien NA, Ginther C, Anderson L, et al. Dacomitinib (PF-00299804), an irreversible Pan-HER inhibitor, inhibits proliferation of HER2-amplified breast cancer cell lines resistant to trastuzumab and lapatinib. Mol Cancer Ther. 2012;11:1978–87.

    Article  CAS  PubMed  Google Scholar 

  37. Engelman JA, Zejnullahu K, Gale CM, Lifshits E, Gonzales AJ, Shimamura T, et al. PF00299804, an irreversible pan-ERBB inhibitor, is effective in lung cancer models with EGFR and ERBB2 mutations that are resistant to gefitinib. Cancer Res. 2007;67:11924–32.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We wish to thank Pfizer for providing dacomitinib for our experiments. This work was supported in part by R01 CA154460-01 and U01 CA176067-01A1 grants from NIH, the Deborah Bunn Alley Foundation, the Tina Brozman Foundation, The Discovery to Cure Foundation, and the Guido Berlucchi Foundation to ADS. This investigation was also supported by NIH Research Grant CA-16359 from the NCI.

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Authors and Affiliations

  1. Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, Rm. 305 LSOG, 333 Cedar Street, PO Box 208063, New Haven, CT, 06520-8063, USA

    Liancheng Zhu, Salvatore Lopez, Stefania Bellone, Jonathan Black, Emiliano Cocco, Tiffany Zigras, Federica Predolini, Elena Bonazzoli, Beatrice Bussi, Zachary Stuhmer, Carlton L. Schwab, Diana P. English, Elena Ratner, Dan-Arin Silasi, Masoud Azodi, Peter E. Schwartz, Thomas J. Rutherford & Alessandro D. Santin

  2. Department of Obstetrics and Gynecology, Shengjing Hospital affiliated to China Medical University, Shenyang, Liaoning, 110004, China

    Liancheng Zhu

  3. Division of Gynecologic Oncology, University Campus Bio-Medico of Roma, 00128, Rome, Italy

    Salvatore Lopez

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  1. Liancheng Zhu
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Correspondence to Alessandro D. Santin.

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Zhu, L., Lopez, S., Bellone, S. et al. Dacomitinib (PF-00299804), a second-generation irreversible pan-erbB receptor tyrosine kinase inhibitor, demonstrates remarkable activity against HER2-amplified uterine serous endometrial cancer in vitro. Tumor Biol. 36, 5505–5513 (2015). https://doi.org/10.1007/s13277-015-3218-4

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