Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs
Abstract Background The human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to ther...
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13058-020-01280-z |
| _version_ | 1819157471322701824 |
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| author | Tejaswini P. Reddy Dong S. Choi Ann C. Anselme Wei Qian Wen Chen Johan Lantto Ivan D. Horak Michael Kragh Jenny C. Chang Roberto R. Rosato |
| author_facet | Tejaswini P. Reddy Dong S. Choi Ann C. Anselme Wei Qian Wen Chen Johan Lantto Ivan D. Horak Michael Kragh Jenny C. Chang Roberto R. Rosato |
| author_sort | Tejaswini P. Reddy |
| collection | DOAJ |
| description | Abstract Background The human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to therapy. This study investigated the effects of Pan-HER (Symphogen, Ballerup, Denmark), a novel mixture of six monoclonal antibodies directed against members of the HER family EGFR, HER2, and HER3, in a preclinical trial of TNBC patient-derived xenografts (PDXs). Methods Fifteen low passage TNBC PDX tumor samples were transferred into the right mammary fat pad of mice for engraftment. When tumors reached an average size of 100–200 mm3, mice were randomized (n ≥ 6 per group) and treated following three 1-week cycles consisting of three times/week intraperitoneal (IP) injection of either formulation buffer (vehicle control) or Pan-HER (50 mg/kg). At the end of treatment, tumors were collected for Western blot, RNA, and immunohistochemistry analyses. Results All 15 TNBC PDXs were responsive to Pan-HER treatment, showing significant reductions in tumor growth consistent with Pan-HER-mediated tumor downmodulation of EGFR and HER3 protein levels and significantly decreased activation of associated HER family signaling pathways AKT and ERK. Tumor regression was observed in five of the models, which corresponded to those PDX tumor models with the highest level of HER family activation. Conclusions The marked effect of Pan-HER in numerous HER family-dependent TNBC PDX models justifies further studies of Pan-HER in TNBC clinical trials as a potential therapeutic option. |
| first_indexed | 2024-12-22T16:09:17Z |
| format | Article |
| id | doaj.art-56ecc7c5000b4303a8e6a4a138fe027f |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-22T16:09:17Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-56ecc7c5000b4303a8e6a4a138fe027f2022-12-21T18:20:31ZengBMCBreast Cancer Research1465-542X2020-05-0122111210.1186/s13058-020-01280-zSimultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXsTejaswini P. Reddy0Dong S. Choi1Ann C. Anselme2Wei Qian3Wen Chen4Johan Lantto5Ivan D. Horak6Michael Kragh7Jenny C. Chang8Roberto R. Rosato9Houston Methodist Cancer Center, Houston Methodist HospitalHouston Methodist Cancer Center, Houston Methodist HospitalHouston Methodist Cancer Center, Houston Methodist HospitalHouston Methodist Cancer Center, Houston Methodist HospitalHouston Methodist Cancer Center, Houston Methodist HospitalSymphogen A/SSymphogen A/STexas A&M Health Science Center College of MedicineHouston Methodist Cancer Center, Houston Methodist HospitalHouston Methodist Cancer Center, Houston Methodist HospitalAbstract Background The human epidermal growth factor receptor (HER) family, notably EGFR, is overexpressed in most triple-negative breast cancer (TNBC) cases and provides cancer cells with compensatory signals that greatly contribute to the survival and development of resistance in response to therapy. This study investigated the effects of Pan-HER (Symphogen, Ballerup, Denmark), a novel mixture of six monoclonal antibodies directed against members of the HER family EGFR, HER2, and HER3, in a preclinical trial of TNBC patient-derived xenografts (PDXs). Methods Fifteen low passage TNBC PDX tumor samples were transferred into the right mammary fat pad of mice for engraftment. When tumors reached an average size of 100–200 mm3, mice were randomized (n ≥ 6 per group) and treated following three 1-week cycles consisting of three times/week intraperitoneal (IP) injection of either formulation buffer (vehicle control) or Pan-HER (50 mg/kg). At the end of treatment, tumors were collected for Western blot, RNA, and immunohistochemistry analyses. Results All 15 TNBC PDXs were responsive to Pan-HER treatment, showing significant reductions in tumor growth consistent with Pan-HER-mediated tumor downmodulation of EGFR and HER3 protein levels and significantly decreased activation of associated HER family signaling pathways AKT and ERK. Tumor regression was observed in five of the models, which corresponded to those PDX tumor models with the highest level of HER family activation. Conclusions The marked effect of Pan-HER in numerous HER family-dependent TNBC PDX models justifies further studies of Pan-HER in TNBC clinical trials as a potential therapeutic option.http://link.springer.com/article/10.1186/s13058-020-01280-zHER familyEGFRTriple-negative breast cancerHER2HER3PDX |
| spellingShingle | Tejaswini P. Reddy Dong S. Choi Ann C. Anselme Wei Qian Wen Chen Johan Lantto Ivan D. Horak Michael Kragh Jenny C. Chang Roberto R. Rosato Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs Breast Cancer Research HER family EGFR Triple-negative breast cancer HER2 HER3 PDX |
| title | Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs |
| title_full | Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs |
| title_fullStr | Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs |
| title_full_unstemmed | Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs |
| title_short | Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs |
| title_sort | simultaneous targeting of her family pro survival signaling with pan her antibody mixture is highly effective in tnbc a preclinical trial with pdxs |
| topic | HER family EGFR Triple-negative breast cancer HER2 HER3 PDX |
| url | http://link.springer.com/article/10.1186/s13058-020-01280-z |
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