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Anti-tumoral activity of the Pan-HER (Sym013) antibody mixture in gemcitabine-resistant pancreatic cancer models.

ABSTRACT: Chemoresistance, particularly to gemcitabine, is a major challenge in pancreatic cancer. The epidermal growth factor receptor (EGFR) and human epidermal growth factor receptors 2 and 3 (HER2, HER3) are expressed in many tumors, and they are relevant therapeutic targets due to their synergistic interaction to promote tumor aggressiveness and therapeutic resistance. Cocktails of antibodies directed against different targets are a promising strategy to overcome these processes. Here, we found by immunohistochemistry that these three receptors were co-expressed in 11% of patients with pancreatic adenocarcinoma. We then developed gemcitabine-resistant pancreatic cancer cell models (SW-1990-GR and BxPC3-GR) and one patient-derived xenograft (PDX2846-GR) by successive exposure to increasing doses of gemcitabine. We showed that expression of EGFR, HER2 and HER3 was increased in these gemcitabine-resistant pancreatic cancer models, and that an antibody mixture against all three receptors inhibited tumor growth in mice and downregulated HER receptors. Finally, we demonstrated that the Pan-HER and gemcitabine combination has an additive effect in vitro and in mice xenografted with the gemcitabine-sensitive or resistant pancreatic models. The mixture of anti-EGFR, HER2 and HER3 antibodies is a good candidate therapeutic approach for gemcitabine-sensitive and -resistant pancreatic cancer.

SUBMITTER: Rabia E

PROVIDER: S-EPMC8078530 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is substantial heterogeneity in the clinical behavior of pancreatic cancer and in its response to therapy. Some of this variation may be due to differences in delivery of cytotoxic therapies between patients and within individual tumors. Indeed, in 12 patients with resectable pancreatic cancer, we previously demonstrated wide inter-patient variability in the delivery of gemcitabine as well as in the mass transport properties of tumors as measured by computed tomography (CT) scans. However, the variability of drug delivery and transport properties within pancreatic tumors is currently unknown. Here, we analyzed regional measurements of gemcitabine DNA incorporation in the tumors of the same 12 patients to understand the degree of intra-tumoral heterogeneity of drug delivery. We also developed a volumetric segmentation approach to measure mass transport properties from the CT scans of these patients and tested inter-observer agreement with this new methodology. Our results demonstrate significant heterogeneity of gemcitabine delivery within individual pancreatic tumors and across the patient cohort, with gemcitabine DNA incorporation in the inner portion of the tumors ranging from 38 to 74% of the total. Similarly, the CT-derived mass transport properties of the tumors had a high degree of heterogeneity, ranging from minimal difference to almost 200% difference between inner and outer portions of the tumor. Our quantitative method to derive transport properties from CT scans demonstrated less than 5% difference in gemcitabine prediction at the average CT-derived transport value across observers. These data illustrate significant inter-patient and intra-tumoral heterogeneity in the delivery of gemcitabine, and highlight how this variability can be reproducibly accounted for using principles of mass transport. With further validation as a biophysical marker, transport properties of tumors may be useful in patient selection for therapy and prediction of therapeutic outcome.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent and aggressive form of pancreatic cancer. Gemcitabine (GEM), the first‑line treatment for PDAC, which alleviates symptoms and enhances the quality of life of patients. However, it is prone to lead to the development of drug resistance during treatment. Interferon (IFN)‑γ exhibits antitumor and immunomodulatory properties. The present study aimed to explore the impact of IFN‑γ on the viability, migration and apoptosis of GEM‑resistant pancreatic cancer cells. Firstly, a GEM‑resistant pancreatic cancer cell line, named PANC‑1/GEM, was constructed. Hematoxylin and eosin staining analyzed the cell morphology, whereas reverse transcription‑quantitative PCR (RT‑qPCR) assessed the expression levels of the drug‑resistance genes multidrug resistance‑associated protein (MRP) and breast cancer resistance protein (BCRP). The MTT assay and cell counting techniques were used to determine the appropriate concentration of IFN‑y and its effects on cell viability. The IFN‑γ‑induced apoptosis of PANC‑1/GEM cells was assessed using an Apoptosis Detection Kit, whereas the impact of IFN‑γ on the migration of these cells was evaluated using a wound‑healing assay. The MTT assay revealed a resistance index of 22.4 in the PANC‑1/GEM cell line. RT‑qPCR indicated that, compared with in wild‑type cells, the PANC‑1/GEM resistant strain exhibited lower MRP and higher BCRP mRNA expression levels. The optimal concentration of IFN‑γ for affecting PANC‑1/GEM cells was determined to be 0.3 µg/ml. At this concentration, IFN‑γ induced PANC‑1/GEM cell apoptosis, along with a notable reduction in migration. Following treatment of PANC‑1/GEM cells with IFN‑γ, MRP expression increased whereas BCRP mRNA expression decreased, indicating a reversal in their drug‑resistance gene expression. In conclusion, IFN‑γ exhibited antitumor immune properties by upregulating MRP and downregulating BCRP expression, reversing drug‑resistance gene expression, and reducing cell viability and migration, while promoting apoptosis in PANC‑1/GEM cells. IFN‑γ could potentially serve as a treatment option for patients with GEM‑resistant pancreatic cancer.

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Anti-tumoral activity of the Pan-HER (Sym013) antibody mixture in gemcitabine-resistant pancreatic cancer models.

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