EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges
2. Receptors Used for Targeted Therapy
- EGFR: The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase belonging to the ErbB family of proteins. Ligand binding is required to activate the tyrosine kinase domain. This activates signaling pathways responsible for cell proliferation, angiogenesis migration, continued existence, and adhesion. Since these pathways are essential for the survival of cancer cells, EGFR is a valuable target in the treatment of colorectal carcinoma metastases .
- VEGFR: The vascular endothelial growth factor receptor (VEGFR) is a tyrosine kinase receptor. Binding of the ligand vascular endothelial growth factor (VEGF) to this receptor leads to the activation of the receptor and promotes vasculogenesis and angiogenesis . VEGF overexpression is observed in 40–60% of colorectal cancers and is related to cancer recurrence and decreased survival .
- FGFR: In several essential physiological mechanisms such as homeostasis of tissue metabolism, embryonic development, endocrine function, and wound repair, angiogenesis fibroblast growth factor (FGFR) signaling pathways are crucially significant . Therapy against FGFR2 and its specific isoforms are being considered as novel treatment options for colorectal cancer patients. By administering shRNA to bind FGFR2, CRC development, invasion, and migration can be reduced .
- HER 2: The type I transmembrane glycoprotein human epidermal growth factor receptor 2 (HER2) is involved in signaling pathways that control cell proliferation, survival, and apoptosis in breast cancer. In 20–25% of breast cancer patients, the HER2 gene is amplified, which is connected to an aggressive phenotype and worse prognosis . The efficacy of HER2-targeted therapy is comparable to that of developing therapeutic options for metastatic colorectal cancer, such as immunotherapy with checkpoint inhibitors and BRAF-directed therapy .
- TGF-β: The signaling pathway that is activated by transforming growth factor-beta (TGF-β) is crucial in the regulation of tissue development, proliferation, differentiation, apoptosis, and homeostasis . TGF-β is also a powerful regulator of cell adhesion, motility, and the composition of the extracellular matrix, all of which are implicated in tumor invasion and metastasis. However, TGF-β signaling also stimulates angiogenesis and immunosuppression. TGF-β signaling breakdown in colorectal cancer cells promotes tumor growth in the early stages, whereas the stimulation thereof may enhance cancer invasion and metastasis. Thus, while TGF-β may be used as a target in nanotherapeutic methods, its dual roles in enhancing and suppressing tumorigenesis require it to be treated in a careful and highly selective manner .
3. Significance of EGFR as a Target
4. Monoclonal Antibodies for EGFR Targeted Therapy
- Cetuximab binds to the second (L2) EGFR domain and consequently blocks downstream signaling by triggering receptor internalization and blocks the interaction between ligand and receptor .
- Through antibody-dependent cell-mediated cytotoxicity (ADCC), cetuximab directs cytotoxic immune effector cells toward EGFR-expressing tumor cells, potentially contributing to its antitumoral impact .
- Cetuximab causes a G1 cell cycle arrest by increasing the cell cycle inhibitor p27kip1 and suppressing proliferating cell nuclear antigen (PCNA) .
- Cetuximab inhibits angiogenesis by restricting the production of pro-angiogenic factors such as interleukin-8, vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (FGF) .
- Induction of apoptosis by cetuximab is mediated through two processes: (a) Increased expression of pro-apoptotic proteins such as BAX, caspase-3, caspase-8, and caspase-9 and (b) inactivation of Bcl-2, which is an anti-apoptotic protein .
5. EGFR Targeted Therapy Using Cetuximab
5.1. Gold Nanoparticles
5.2. Iron Oxide Nanoparticles
5.3. Polymeric Nanoparticles
5.4. Protein Nanoparticles
5.7. Carbon Nanotubes
5.8. Quantum Dots
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
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|Name of the Antibody||Antibody Type||Disease||Molecular Weight||Mechanism of Action||Market Status||Side Effects|
|Head and neck cancer|
Metastatic colorectal cancer
|145.7816 kDa||(1) Binds to domain III of EGFR receptor and prevents the conformational change required for EGFR activation|
(2) Induce apoptosis and decrease matrix metalloproteinase and VGEF
|Marketed||rash, itching, dry or cracked skin, nail changes, headache, diarrhea, nausea, vomiting, upset stomach, weight loss, weakness, and respiratory, skin, and mouth infections.|
|Metastatic colorectal cancer||147 kDa||(1) Binds to domain III of EGFR receptor and prevents the conformational change required for EGFR activation||Marketed||Skin reactions, Fatigue, General deterioration, Abdominal pain, Nausea, Diarrhea, Vomiting, Swelling in hands or feet, Cough, Dry skin, Inflammation of the bed of the fingernails, Eye irritation|
|Carriers||Formulation||Method of Antibody conjugation/coating||Drug||Target cells/Animal models||Disease/Application||Significance|
|Gold nanoparticles||Tetrachloroauric acid, sodium citrate, and cetuximab||Physical adsorption||-||Caco-2, HT-29 and HCT-116||Colorectal cancer||Tight junction modulation by Gold nanoparticles aid in drug delivery. Improved cell death mediated by cetuximab .|
|Gold nanoparticles||Tetrachloroauric acid, sodium citrate, s 5,50 -dithiobis-(2-nitrobenzoic acid), 7-mercapto4-methyl coumarin, 2,3,5,6-tetrafluoro-4-mercaptobenzoic acid, and cetuximab||Physical adsorption||-||HT-29||Colorectal cancer||Expression of cell surface biomarkers such as MCAM, HER3, and EpCAM with more heterogenicity .|
|Magneto fluorescent silica nanoparticles||Polyvinylpyrrolidone, ferrite, 2- [methoxy- (polyethyleneoxy)propyl] trimethoxysilane, (3-trimethoxysilil) propyl diethylene triamine, and cetuximab antibody fragment||Physical adsorption||-||HCT 116, H520 cells, HT 29, SW620, and BALB/c nude male mice||Colorectal cancer||Considerable MRI signal changes|
Local concentration of MFSN-Ctx amplified by an external magnetic field .
|Ca-alginate-beads||sodium alginate, calcium chloride, Octreotide, and Cetuximab||solvent evaporation method||Octreotide||MCF-7, HepG-2, and HCT-116||Breast cancer, Hepatocellular carcinoma, and colorectal cancer||Target a specific area in Gastro-Intestinal Tract|
Specifically penetrates somatostatin expressing cells and releases octreotide .
|Chitosan-Pectin nanoparticles||Chitosan, pectin, curcumin and cetuximab||EDC–NHS chemistry||Curcumin||Caco-2, and HCT-116.||Colorectal cancer||EGFR overexpressing cancer cell line had stronger anti-cancer activity|
Cetuximab enhanced the nanoparticle uptake .
|Γ Poly (glutamic Acid) nanoparticles||Γ Poly (glutamic Acid), chitosan, docetaxel, rhodamine-123, and cetuximab.||EDC–NHS chemistry||Docetaxel||HT-29, IEC-6, and Swiss Albino mice||Colorectal cancer||A two-fold increase in nanoparticle uptake in EGFR+ve cells|
increased cytotoxicity antiproliferative activity due to cell cycle arrest at G2/M phase .
|PLGA nanoparticles||Poly (lactic-co-glycolic acid), Temozolomide, and cetuximab.||EDC–NHS chemistry||Temozolomide||U-87MG, SK-Mel 28, and SW480||Brain cancer, Skin cancer, and Colorectal cancer||Improved cellular uptake|
Increased apoptotic impact
Upregulation of γ-H2A .
|BSA nanoparticles||MC-Val-Cit-PAB-PNP, Doxorubicin, and cetuximab||Direct coupling||Doxorubicin||RKO, d LS174, and BALB/c nude mice||Colorectal cancer||Increased the duration of doxorubicin uptake into cells|
Improved accumulation of the drug in tumors
Lowered systemic toxicity .
|BSA nanoparticles||BSA, doxorubicin, and cetuximab||Direct coupling||Doxorubicin||RKO and LS174 t||Colorectal cancer||Significant cytotoxic activity of doxorubicin in EGFR overexpressing cells with increased selectivity and low toxicity .|
|Liposomes||Oxaliplatin, and Fab of cetuximab||Maleimide chemistry||Oxaliplatin||HCT-116, HT-29, SW-480, SW-620, and nude mice||Colorectal cancer||Effective delivery of intracellular L-OH|
Resistance to L-OH was reversed when targeted liposomes are used
Fab’ ligand targeted liposomes were more efficacious in antitumor activity than cetuximab targeted liposomes .
|Cerosomes||1,2-Distearoyl-sn-glycero-3- phosphoethanolamine-n-[poly(ethylene glycol)]-hydroxy succi- nimide, cetuximab, and porphyrin||Direct Coupling||Porphyrin||CT26-fLuc, and Balb/c mice||Colorectal cancer||Preferential accumulation of EGFR-CPIG at tumor locations|
The combination of EPR effect and the active tumor targeting capability of EGFR increase the tumour targeting capacity .
|Micelles||ε-caprolactone, Methoxy poly ethylene glycol, Poly ethylene glycol monoethyl ether maleimide, (DTPA dianhydride, and cetuximab||Chemical modification |
(Near infrared dye)
|HCT-116, SW-620, and nude mice||Colorectal cancer||Highest contrast of NIRF signals was obtained between HCT-116 and SW-620 tumors. Increased delivery of IR-780 and enhanced photo thermal therapy was observed in HCT-116 tumors (EGFR +ve ) .|
|Carbon nanotubes||Carbon nanotubes, SWNT-COOH, NH2-PEGNH2, and cetuximab||EDC–NHS chemistry||SN38|
(Topoisomerase I inhibitor), and Pyrene 38
|HCT116, HT29, and SW-620||Colorectal cancer||The targeting ability and delivery of SN38 by Cetuximab conjugated SWNT25/py38 was enhanced in EGFR +ve colorectal cancer cell line. Clatherin-dependent endocytosis was responsible for uptake of SWNT25/py38 .|
|Quantum Dots||Silver nitrate,5-aminolevulinic acid hydrochloride,|
2-Mercaptopropionic acid, Sodium sulfide,
|EDC–NHS chemistry||ALA||HCT116, HT29, and SW-480||Colorectal cancer||The targeting ability of quantum dots was observed to increase with increased EGFR expression and there is a strong intracellular NIR signals .|
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Janani, B.; Vijayakumar, M.; Priya, K.; Kim, J.H.; Prabakaran, D.S.; Shahid, M.; Al-Ghamdi, S.; Alsaidan, M.; Othman Bahakim, N.; Hassan Abdelzaher, M.; Ramesh, T. EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges. Vaccines 2022, 10, 499. https://doi.org/10.3390/vaccines10040499
Janani B, Vijayakumar M, Priya K, Kim JH, Prabakaran DS, Shahid M, Al-Ghamdi S, Alsaidan M, Othman Bahakim N, Hassan Abdelzaher M, Ramesh T. EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges. Vaccines. 2022; 10(4):499. https://doi.org/10.3390/vaccines10040499Chicago/Turabian Style
Janani, Balakarthikeyan, Mayakrishnan Vijayakumar, Kannappan Priya, Jin Hee Kim, D. S. Prabakaran, Mohammad Shahid, Sameer Al-Ghamdi, Mohammed Alsaidan, Nasraddin Othman Bahakim, Mohammad Hassan Abdelzaher, and Thiyagarajan Ramesh. 2022. "EGFR-Based Targeted Therapy for Colorectal Cancer—Promises and Challenges" Vaccines 10, no. 4: 499. https://doi.org/10.3390/vaccines10040499