Lani
03-25-2010, 12:56 AM
acquired resistance to lapatinib (herceptin?).
It may be upregulated in response to her2 targetted agents and perhaps a combined targetting could get around this problem/
Interestingly grb7 is one of the 21 genes in the OncoDx test
Grb7 Upregulation Is a Molecular Adaptation to HER2 Signaling Inhibition Due to Removal of Akt-Mediated Gene Repression
Alessio Nencioni1*, Michele Cea1, Anna Garuti1, Mario Passalacqua2,3, Lizzia Raffaghello4, Debora Soncini1, Eva Moran1, Gabriele Zoppoli1, Vito Pistoia4, Franco Patrone1, Alberto Ballestrero1
1 Department of Internal Medicine, Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, 2 Department of Experimental Medicine-Biochemistry Section, Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, 3 Italian Institute of Biostructures and Biosystems (INBB), Rome, Italy, 4 Laboratory of Oncology, Department of Experimental and Laboratory Medicine, G. Gaslini Institute, Genova, Italy
Abstract
The efficacy of anti-HER2 therapeutics, such as lapatinib and trastuzumab, is limited by primary and acquired resistance. Cellular adaptations that allow breast cancer cell to survive prolonged HER2 inhibition include de-repression of the transcription factor FOXO3A with consequent estrogen receptor activation, and/or increased HER3 signaling. Here, we used low-density arrays, quantitative PCR, and western blotting to determine how HER2 signaling inhibition with lapatinib or PI3K inhibitors affects the expression of genes involved in breast cancer metastatic spread and overall prognosis. Retroviral transgenesis was used to express constitutively active forms of Akt in the HER2+ breast cancer cell line SKBR3, and Grb7 in MCF7 cells. Specific gene silencing was obtained by siRNAs transfection. A murine BT474 xenograft cancer model was used to assess the effect of lapatinib on gene expression in vivo. We found that lapatinib induces upregulation of Grb7, an adaptor protein involved in receptor tyrosine kinase signaling and promoting cell survival and cell migration. Grb7 upregulation induced by lapatinib was found to occur in cancer cells in vitro and in vivo. We demonstrate that Grb7 upregulation is recreated by PI3K inhibitors while being prevented by constitutively active Akt. Thus, Grb7 is repressed by PI3K signaling and lapatinib-mediated Akt inhibition is responsible for Grb7 de-repression. Finally, we show that Grb7 removal by RNA-interference reduces breast cancer cell viability and increases the activity of lapatinib. In conclusion, Grb7 upregulation is a potentially adverse consequence of HER2 signaling inhibition. Preventing Grb7 accumulation and/or its interaction with receptor tyrosine kinases may increase the benefit of HER2-targeting drugs.
http://www.plosone.org.laneproxy.stanford.edu/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009024
It may be upregulated in response to her2 targetted agents and perhaps a combined targetting could get around this problem/
Interestingly grb7 is one of the 21 genes in the OncoDx test
Grb7 Upregulation Is a Molecular Adaptation to HER2 Signaling Inhibition Due to Removal of Akt-Mediated Gene Repression
Alessio Nencioni1*, Michele Cea1, Anna Garuti1, Mario Passalacqua2,3, Lizzia Raffaghello4, Debora Soncini1, Eva Moran1, Gabriele Zoppoli1, Vito Pistoia4, Franco Patrone1, Alberto Ballestrero1
1 Department of Internal Medicine, Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, 2 Department of Experimental Medicine-Biochemistry Section, Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy, 3 Italian Institute of Biostructures and Biosystems (INBB), Rome, Italy, 4 Laboratory of Oncology, Department of Experimental and Laboratory Medicine, G. Gaslini Institute, Genova, Italy
Abstract
The efficacy of anti-HER2 therapeutics, such as lapatinib and trastuzumab, is limited by primary and acquired resistance. Cellular adaptations that allow breast cancer cell to survive prolonged HER2 inhibition include de-repression of the transcription factor FOXO3A with consequent estrogen receptor activation, and/or increased HER3 signaling. Here, we used low-density arrays, quantitative PCR, and western blotting to determine how HER2 signaling inhibition with lapatinib or PI3K inhibitors affects the expression of genes involved in breast cancer metastatic spread and overall prognosis. Retroviral transgenesis was used to express constitutively active forms of Akt in the HER2+ breast cancer cell line SKBR3, and Grb7 in MCF7 cells. Specific gene silencing was obtained by siRNAs transfection. A murine BT474 xenograft cancer model was used to assess the effect of lapatinib on gene expression in vivo. We found that lapatinib induces upregulation of Grb7, an adaptor protein involved in receptor tyrosine kinase signaling and promoting cell survival and cell migration. Grb7 upregulation induced by lapatinib was found to occur in cancer cells in vitro and in vivo. We demonstrate that Grb7 upregulation is recreated by PI3K inhibitors while being prevented by constitutively active Akt. Thus, Grb7 is repressed by PI3K signaling and lapatinib-mediated Akt inhibition is responsible for Grb7 de-repression. Finally, we show that Grb7 removal by RNA-interference reduces breast cancer cell viability and increases the activity of lapatinib. In conclusion, Grb7 upregulation is a potentially adverse consequence of HER2 signaling inhibition. Preventing Grb7 accumulation and/or its interaction with receptor tyrosine kinases may increase the benefit of HER2-targeting drugs.
http://www.plosone.org.laneproxy.stanford.edu/article/info%3Adoi%2F10.1371%2Fjournal.pone.0009024