Abstract |
Current treatment options for patients with advanced colorectal cancers include anti-EGFR/HER1 therapy with the blocking antibody cetuximab. Although a subset of patients with KRAS WT disease initially respond to the treatment, resistance develops in almost all cases. Relapse has been associated with the production of the ligand heregulin ( HRG) and/or compensatory signaling involving the receptor tyrosine kinases HER2 and HER3. Here, we provide evidence that triple-HER receptor blockade based on a newly developed bispecific EGFR×HER3-targeting antibody (scDb-Fc) together with the HER2-blocking antibody trastuzumab effectively inhibited HRG-induced HER receptor phosphorylation, downstream signaling, proliferation, and stem cell expansion of DiFi and LIM1215 colorectal cancer cells. Comparative analyses revealed that the biological activity of scDb-Fc plus trastuzumab was sometimes even superior to that of the combination of the parental antibodies, with PI3K/Akt pathway inhibition correlating with improved therapeutic response and apoptosis induction as seen by single-cell analysis. Importantly, growth suppression by triple-HER targeting was recapitulated in primary KRAS WT patient-derived organoid cultures exposed to HRG. Collectively, our results provide strong support for a pan-HER receptor blocking approach to combat anti-EGFR therapy resistance of KRAS WT colorectal cancer tumors mediated by the upregulation of HRG and/or HER2/HER3 signaling.
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Authors | Alexander Rau, Nicole Janssen, Lennart Kühl, Thomas Sell, Svetlana Kalmykova, Thomas E Mürdter, Marc-H Dahlke, Christine Sers, Markus Morkel, Matthias Schwab, Roland E Kontermann, Monilola A Olayioye |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 21
Issue 5
Pg. 799-809
(05 04 2022)
ISSN: 1538-8514 [Electronic] United States |
PMID | 35247930
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | ©2022 American Association for Cancer Research. |
Chemical References |
- Neuregulin-1
- EGFR protein, human
- ErbB Receptors
- Receptor, ErbB-2
- Receptor, ErbB-3
- Proto-Oncogene Proteins p21(ras)
- Trastuzumab
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Topics |
- Cell Line, Tumor
- Colorectal Neoplasms
(pathology)
- Drug Resistance, Neoplasm
- ErbB Receptors
(metabolism)
- Humans
- Neoplasm Recurrence, Local
- Neuregulin-1
(metabolism)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Proto-Oncogene Proteins p21(ras)
(metabolism)
- Receptor, ErbB-2
(metabolism)
- Receptor, ErbB-3
- Trastuzumab
(pharmacology)
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