Panitumumab interaction with TAS‐102 leads to combinational anticancer effects via blocking of EGFR‐mediated tumor response to trifluridine
Open accessAbstract
Panitumumab is a monoclonal antibody developed against the human epidermal growth factor receptor (EGFR).TAS‐102 is a novel chemotherapeutic agent containing trifluridine (FTD) as the active cytotoxic component. Both panitumumab and TAS‐102 have been approved for the treatment of metastatic colorectal cancer. In this study, we revealed the mechanism underlying the anticancer effects of panitumumab/TAS‐102 combination using preclinical models. Panitumumab/FTD cotreatment showed additive antiproliferative effects in LIM 1215 and synergistic antiproliferative effects in SW 48 colon cancer cells. Consistent with the in vitro effects, panitumumab/TAS‐102 combination caused tumor regression in LIM 1215 and COL‐01‐JCK colon cancer patient‐derived xenograft models. In LIM 1215 cells,FTD induced extracellular signal‐regulated kinase (ERK)/protein kinase B (AKT)/signal transducer and activator of transcription 3 (STAT 3) phosphorylation and subsequent serine/threonine phosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumab and the tyrosine kinase inhibitor erlotinib reduced the basal level of EGFR tyrosine phosphorylation and reversed FTD‐induced ERK/AKT/STAT 3 and EGFR serine/threonine phosphorylation. These results suggested that FTD in combination with the basal activity of EGFR tyrosine kinase induced downstream prosurvival signaling through ERK/AKT/STAT 3 phosphorylation. Collectively, we propose that panitumumab interacts with FTD by targeting EGFR‐mediated adaptive responses, thereby exerting anticancer effects when used in combination with TAS‐102. These preclinical findings provide a compelling rationale for evaluating the combination of anti‐EGFR antibodies with TAS‐102 against metastatic colorectal cancer.
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Panitumumab/TAS-102 cotreatment showed additive antiproliferative effects in LIM1215 CRC cells in vitro and in vivo.
“Panitumumab/TAS-102 cotreatment showed additive antiproliferative effects in LIM1215 CRC cells in vitro and in vivo [59].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [59]
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- Authors
- Baba, Y., Tamura, T., Satoh, Y., Gotou, M., Sawada, H., Ebara, S., Shibuya, K., Soeda, J., & Nakamura, K.
- Affiliations
- Takeda (Japan) (JP)
- Medical Affairs Department Takeda Pharmaceutical Company Limited Tokyo Japan
- Corresponding author
- Nakamura, Kazuhide
- Venue
- Molecular Oncology
- Publisher
- Wiley
- Published
- 2017-05-30
- Volume
- 11
- Issue
- 8
- Pages
- 1065-1077
- ISSN
- 1574-7891 (ISSN-L)
- 1878-0261
- PMC
- PMC5537908
- OpenAlex
- W2613038127
- Cited by
- 23
- References
- 49
- Citations by year
- 2026: 2 · 2024: 3 · 2023: 3 · 2022: 2 · 2021: 6 · 2020: 1 · 2018: 4 · 2017: 2
- FWCI
- 0.84
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Oncology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- panitumumab, trifluridine/tipiracil, trifluridine, EGFR, metastatic colorectal cancer, combination therapy, adaptive resistance, erlotinib, patient-derived xenografts, colon cancer cells, antiproliferative activity
- MeSH terms
- Panitumumab, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Colonic Neoplasms, Drug Combinations, Drug Screening Assays, Antitumor, Humans, Pyrrolidines, Thymine, Trifluridine, Uracil, Cell Line, Tumor, ErbB Receptors
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