Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer
Abstract HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and a...
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Wiley
2019-03-01
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| Series: | Cancer Medicine |
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| Online Access: | https://doi.org/10.1002/cam4.1995 |
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| author | Satomi Watanabe Kimio Yonesaka Junko Tanizaki Yoshikane Nonagase Naoki Takegawa Koji Haratani Hisato Kawakami Hidetoshi Hayashi Masayuki Takeda Junji Tsurutani Kazuhiko Nakagawa |
| author_facet | Satomi Watanabe Kimio Yonesaka Junko Tanizaki Yoshikane Nonagase Naoki Takegawa Koji Haratani Hisato Kawakami Hidetoshi Hayashi Masayuki Takeda Junji Tsurutani Kazuhiko Nakagawa |
| author_sort | Satomi Watanabe |
| collection | DOAJ |
| description | Abstract HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2‐positive breast cancer. The anti‐HER2 antibody pertuzumab and anti‐HER3 antibody patritumab both target this heregulin–HER3‐HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab‐resistant HER2‐positive breast cancer. HER2‐positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3‐HRG, BT474‐HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474‐HRG and an intrinsic heregulin‐expressing and HER2‐positive JIMT‐1 xenograft models. SKBR3‐HRG and BT474‐HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin‐expressing BT474‐HRG and JIMT‐1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically. |
| format | Article |
| id | doaj-art-680367125353421e83c0123c3cb7353f |
| institution | Kabale University |
| issn | 2045-7634 |
| language | English |
| publishDate | 2019-03-01 |
| publisher | Wiley |
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| series | Cancer Medicine |
| spelling | doaj-art-680367125353421e83c0123c3cb7353f2025-01-31T08:47:43ZengWileyCancer Medicine2045-76342019-03-01831258126810.1002/cam4.1995Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancerSatomi Watanabe0Kimio Yonesaka1Junko Tanizaki2Yoshikane Nonagase3Naoki Takegawa4Koji Haratani5Hisato Kawakami6Hidetoshi Hayashi7Masayuki Takeda8Junji Tsurutani9Kazuhiko Nakagawa10Department of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanDepartment of Medical Oncology Kindai University Faculty of Medicine Osaka‐Sayama, Osaka JapanAbstract HER2‐targeted therapy, especially the anti‐HER2 antibody trastuzumab, is standard for HER2‐positive breast cancer; however, its efficacy is limited in a subpopulation of patients. HER3 ligand (heregulin)‐dependent HER2‐HER3 interactions play a critical role in the evasion of apoptosis and are therefore a target for oncotherapy to treat HER2‐positive breast cancer. The anti‐HER2 antibody pertuzumab and anti‐HER3 antibody patritumab both target this heregulin–HER3‐HER2 complex in different ways. This study examined the anticancer efficacy of dual HER2 and HER3 blockade in trastuzumab‐resistant HER2‐positive breast cancer. HER2‐positive SKBR3 or BT474 cells overexpressing heregulin (SKBR3‐HRG, BT474‐HRG) were used to evaluate the efficacy of trastuzumab, pertuzumab, and patritumab in vitro by performing cell viability, immunoblotting, and clonogenic assays. The effects of these agents were then evaluated in vivo using BT474‐HRG and an intrinsic heregulin‐expressing and HER2‐positive JIMT‐1 xenograft models. SKBR3‐HRG and BT474‐HRG cells lost sensitivity to trastuzumab, which was accompanied by Akt activation. Unexpectedly, trastuzumab in combination with pertuzumab or patritumab also showed limited efficacy toward these cells. In contrast, trastuzumab/pertuzumab/patritumab triple treatment demonstrated potent anticancer efficacy, concomitant with strong repression of Akt. Finally, in heregulin‐expressing BT474‐HRG and JIMT‐1 xenograft models, the addition of pertuzumab and patritumab to trastuzumab also enhanced antitumor efficacy leading to tumor regression. The current study found that triple blockade of HER2 and HER3 using trastuzumab, pertuzumab, and patritumab could overcome resistance to trastuzumab therapy in heregulin‐expressing and HER2‐positive breast cancer, which could be exploited clinically.https://doi.org/10.1002/cam4.1995heregulin (HRG)human epidermal growth factor receptor 2 (HER2)human epidermal growth factor receptor 3 (HER3)neuregulin (NRG)patritumab (U3‐1287) |
| spellingShingle | Satomi Watanabe Kimio Yonesaka Junko Tanizaki Yoshikane Nonagase Naoki Takegawa Koji Haratani Hisato Kawakami Hidetoshi Hayashi Masayuki Takeda Junji Tsurutani Kazuhiko Nakagawa Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer Cancer Medicine heregulin (HRG) human epidermal growth factor receptor 2 (HER2) human epidermal growth factor receptor 3 (HER3) neuregulin (NRG) patritumab (U3‐1287) |
| title | Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer |
| title_full | Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer |
| title_fullStr | Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer |
| title_full_unstemmed | Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer |
| title_short | Targeting of the HER2/HER3 signaling axis overcomes ligand‐mediated resistance to trastuzumab in HER2‐positive breast cancer |
| title_sort | targeting of the her2 her3 signaling axis overcomes ligand mediated resistance to trastuzumab in her2 positive breast cancer |
| topic | heregulin (HRG) human epidermal growth factor receptor 2 (HER2) human epidermal growth factor receptor 3 (HER3) neuregulin (NRG) patritumab (U3‐1287) |
| url | https://doi.org/10.1002/cam4.1995 |
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