Targeting EGFR/HER2 pathways enhances the antiproliferative effect of gemcitabine in biliary tract and gallbladder
Ymera Pignochino1, Ivana Sarotto, Caterina Peraldo-Neia
1Department of Medical Oncology, University of Torino Medical School, Institute for Cancer Research and Treatment, Candiolo, Italy. ymera.pignochino@ircc.it
Background:
Advanced biliary tract carcinomas (BTCs) have poor prognosis and limited therapeutic options. Therefore, it is crucial to combine standard therapies with molecular targeting. In this study EGFR, HER2, and their molecular transducers were analysed in terms of mutations, amplifications and over-expression in a BTC case series. Furthermore, we tested the efficacy of drugs targeting these molecules, as single agents or in combination with gemcitabine, the standard therapeutic agent against BTC.
Methods:
Immunohistochemistry, FISH and mutational analysis were performed on 49 BTC samples of intrahepatic (ICCs), extrahepatic (ECCs), and gallbladder (GBCs) origin. The effect on cell proliferation of different EGFR/HER2 pathway inhibitors as single agents or in combination with gemcitabine was investigated on BTC cell lines. Western blot analyses were performed to investigate molecular mechanisms of targeted drugs.
Results:
EGFR is expressed in 100% of ICCs, 52.6% of ECCs, and in 38.5% of GBCs. P-MAPK and p-Akt are highly expressed in ICCs (>58% of samples), and to a lower extent in ECCs and GBCs (<46%), indicating EGFR pathway activation. HER2 is overexpressed in 10% of GBCs (with genomic amplification), and 26.3% of ECCs (half of which has genomic amplification). EGFR or its signal transducers are mutated in 26.5% of cases: 4 samples bear mutations of PI3K (8.2%), 3 cases (6.1%) in K-RAS, 4 (8.2%) in B-RAF, and 2 cases (4.1%) in PTEN, but no loss of PTEN expression is detected. EGI-1 cell line is highly sensitive to gemcitabine, TFK1 and TGBC1-TKB cell lines are responsive and HuH28 cell line is resistant. In EGI-1 cells, combination with gefitinib further increases the antiproliferative effect of gemcitabine. In TFK1 and TGBC1-TKB cells, the efficacy of gemcitabine is increased with addiction of sorafenib and everolimus. In TGBC1-TKB cells, lapatinib also has a synergic effect with gemcitabine. HuH28 becomes responsive if treated in combination with erlotinib. Moreover, HuH28 cells are sensitive to lapatinib as a single agent. Molecular mechanisms were confirmed by western blot analysis.
Conclusion:
These data demonstrate that EGFR and HER2 pathways are suitable therapeutic targets for BTCs. The combination of gemcitabine with drugs targeting these pathways gives encouraging results and further clinical studies could be warranted.
Insights
Targeting the EGFR and HER2 pathways shows promise for advanced biliary tract carcinomas (BTCs). Combining gemcitabine with targeted therapies like gefitinib, sorafenib, everolimus, and lapatinib enhances anti-cancer effects in BTC models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Advanced biliary tract carcinomas (BTCs) present a significant clinical challenge with poor prognoses and limited treatment options.
- There is a critical need to integrate standard therapies with molecularly targeted agents for improved patient outcomes.
- This study investigates the role of the Epidermal Growth Factor Receptor (EGFR) and Human Epidermal growth factor Receptor 2 (HER2) pathways in BTC.
Purpose of the Study:
- To analyze mutations, amplifications, and overexpression of EGFR, HER2, and their downstream effectors in a series of BTC cases.
- To evaluate the efficacy of drugs targeting these pathways, both as monotherapies and in combination with gemcitabine, the standard BTC treatment.
Main Methods:
- Immunohistochemistry, Fluorescence In Situ Hybridization (FISH), and mutational analysis were performed on 49 BTC samples (intrahepatic, extrahepatic, and gallbladder).
- The impact of EGFR/HER2 pathway inhibitors, alone and with gemcitabine, on BTC cell line proliferation was assessed.
- Western blot analysis was utilized to elucidate the molecular mechanisms underlying the targeted drug effects.
Main Results:
- EGFR expression was observed in all intrahepatic cholangiocarcinomas (ICCs) and in a significant proportion of extrahepatic cholangiocarcinomas (ECCs) and gallbladder carcinomas (GBCs).
- Evidence of EGFR pathway activation (p-MAPK, p-Akt) and HER2 overexpression/amplification was found in various BTC subtypes.
- Combinations of gemcitabine with EGFR/HER2 inhibitors demonstrated synergistic or additive anti-proliferative effects in sensitive BTC cell lines, with some agents showing efficacy even as single agents.
Conclusions:
- The EGFR and HER2 pathways represent viable therapeutic targets for biliary tract carcinomas.
- Combining gemcitabine with targeted agents against these pathways yields promising results in preclinical models.
- Further clinical investigation into these combination strategies for BTC treatment is warranted.
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