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Evolution of the predictive markers amphiregulin and epiregulin mRNAs during long-term cetuximab treatment of KRAS wild-type tumor cells

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Summary

Molecular mechanisms other than activating KRAS mutations should underlie the occurrence of weaker versus stronger responses to cetuximab (CTX) in EGFR-dependent carcinomas with either an intact KRAS signaling or in which KRAS mutations do not predict CTX efficacy. We hypothesized that KRAS wild-type (WT) tumor cell-line models chronically adapted to grow in the presence of CTX could be interrogated to establish if the positive predictive value of the mRNAs coding for the EGFR ligands amphiregulin (AR) and epiregulin (EPI) could be significantly altered during and/or after treatment with CTX. Gene expression analyses using real-time (kinetic) RT-PCR were performed to monitor the transcriptional evolution of EGFR ligands EGF, TGFα, AR, BTC, EPI, NRG and HB-EGF in experimental modes induced to exhibit acquired resistance to the mono-HER1 inhibitor CTX, the mono-HER2 inhibitor trastuzumab (Tzb) or the dual HER1/HER2 inhibitor lapatinib (LPT). Gene expression signatures for EGFR ligands distinctively related to the occurrence of unresponsiveness to CTX, Tzb or LPT, with minimal overlap between them. CTX’s molecular functioning largely depended on the overproduction of the mRNAs coding for the EGFR ligands AR and EPI. Thus, a dramatic down-regulation of AR/EPI mRNA expression occurred upon loss of CTX efficacy in EGFR-positive tumor cells with an intact regulation of RAS signaling. Unlike KRAS mutations, which are informative of unresponsiveness to CTX solely in mCRC, our hypothesis-generating data suggest that expression status of AR and EPI mRNAs might be evaluated as dynamic predictors of response in KRAS WT patients receiving any CTX-based therapy.

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Acknowledgments

Alejandro Vazquez-Martin is the recipient of a “Sara Borrell” post-doctoral contract (CD08/00283, Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria –FIS-, Spain). Work at Menendez’ laboratory is supported in part by the Instituto de Salud Carlos III (Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria –FIS-, Spain, Grants CP05-00090 and PI06-0778 and RD06-0020-0028), the Fundación Científica de la Asociación Española Contra el Cáncer (AECC, Spain), and by the Ministerio de Ciencia e Innovación (SAF2009-11579, Plan Nacional de I+D+ I, MICINN, Spain).

Conflicts of interest

Cristina Oliveras-Ferraros received a research salary, in part, from a Grant Award by the “Fundación Salud 2000”, which is promoted by Merck Serono (Madrid, Spain). All other authors: None to declare.

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Authors and Affiliations

  1. Unit of Translational Research, Catalan Institute of Oncology, Girona, Catalonia, Spain

    Cristina Oliveras-Ferraros, Alejandro Vazquez-Martin, Silvia Cufí & Javier A. Menendez

  2. Girona Biomedical Research Institute (IdIBGi), Girona, Catalonia, Spain

    Cristina Oliveras-Ferraros, Anna Massaguer Vall-llovera, Dolors Carrion Salip, Alejandro Vazquez-Martin, Silvia Cufí, Bernardo Queralt, Begoña Martin-Castillo, Joan Brunet, Rafael de Llorens & Javier A. Menendez

  3. Biochemistry and Molecular Biology Unit, Dept. of Biology, University of Girona, Girona, Catalonia, Spain

    Anna Massaguer Vall-llovera, Dolors Carrion Salip & Rafael de Llorens

  4. Medical Oncology, Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain

    Bernardo Queralt & Joan Brunet

  5. Unit of Clinical Research, Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain

    Begoña Martin-Castillo

  6. Dr. Josep Trueta University Hospital, Avenida de França s/n, 17007, Girona, Catalonia, Spain

    Javier A. Menendez

Authors
  1. Cristina Oliveras-Ferraros
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  2. Anna Massaguer Vall-llovera
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  3. Dolors Carrion Salip
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  4. Alejandro Vazquez-Martin
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  9. Rafael de Llorens
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  10. Javier A. Menendez
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Corresponding author

Correspondence to Javier A. Menendez.

Additional information

Cristina Oliveras-Ferraros and Anna Massaguer Vall-llovera contributed equally to this research and are listed in random order. Javier A. Menendez and Rafael de Llorens: Co-senior authors

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Oliveras-Ferraros, C., Vall-llovera, A.M., Salip, D.C. et al. Evolution of the predictive markers amphiregulin and epiregulin mRNAs during long-term cetuximab treatment of KRAS wild-type tumor cells. Invest New Drugs 30, 846–852 (2012). https://doi.org/10.1007/s10637-010-9612-2

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  • DOI: https://doi.org/10.1007/s10637-010-9612-2

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