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Innovative Medicines & Omics Tyrosine kinases: Structure, mechanism, and therapeutics

Table 5. List of approved monoclonal antibodies targeting EGFR 148
mAbs Nature of molecule Binds to Antibody-dependent cell- Mechanism Clinical approval
mediated cytotoxicity
Nimotuzumab Humanized, mouse Extracellular domain of - Prevents binding of EGF Yes, phase III
mAb EGFR (approved for treating
HNSCC in non-USA
countries)
Zalutumumab Humanized IgG1 Extracellular domain of Yes Prevents the binding of Yes, phase III
EGFR ligands such as EGF and
TGFα, thereby inhibiting
EGFR signaling
Trastuzumab Humanized IgG1 Juxtamembrane domain Yes Inhibits HER2 homodimers Yes
IV and ligand-independent
HER2–HER3 dimers
Pertuzumab Humanized IgG1 Heterodimerization Yes Inhibits ligand-induced Yes
domain II HER2-containing
heterodimers
Cetuximab Humanized IgG1 Extracellular domain of Yes Prevents the binding of Yes
EGFR ligands like EGF and TGFα,
thereby inhibiting EGFR
signaling
Panitumumab Humanized IgG1 Extracellular domain of Yes Prevents the binding of Yes, phase III
EGFR ligands such as EGF and
TGFα, thereby inhibiting
EGFR signaling
Abbreviations: EGF: Epidermal growth factor; EGFR: Epidermal growth factor receptor; HER: Human epidermal growth factor receptor;
HNSCC: Head-and-neck squamous cell carcinoma; mAb: Monoclonal antibody; NSCLC: Non-small cell lung cancer; TGFα: Transforming growth
factor alpha; IgG1: Immunoglobulin G1.
EGFR-TKIs and also exploring combination therapies. trastuzumab. Another potential explanation for the
167
For instance, EGFR-TKIs combined with programmed development of trastuzumab resistance is its ability to
death ligand 1 antibodies with chemotherapy have shown bind to hyaluronan and CD44, a transmembrane receptor
significant survival benefits to patients suffering from that can hinder trastuzumab’s access to HER2. A clinical
168
EGFR mutation-driven drug resistance in cancers. The study was conducted to analyze sensitivity to trastuzumab
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FDA-approved TKI and NTKI inhibitors used in cancer treatment and reported in the study on 46 patients with
therapy are listed in Tables 3 and 4. breast cancer, in which 11.1% of patients responded to
trastuzumab (expressing p95HER2), with 51.4% of the
7. Resistance and the mechanism of patients who expressed p185HER2 achieving clinical
developing resistance to therapy response. Lapatinib, a small molecule that can inhibit
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Trastuzumab (Herceptin), a therapeutic antibody used both HER2 and EGFR kinase, was tested in p95HER2
to treat breast cancer, often encounters resistance in preclinical studies to prevent HER2 signaling loss of
169
patients. It binds to an epitope in the juxtamembrane the trastuzumab binding site. Coupled lapatinib with
region of the HER2 RTKs. Upon binding, trastuzumab trastuzumab has been clinically shown to be effective in
170
induces uncoupling of ligand-independent HER2-HER3 patients with stage IV HER-overexpressing breast cancer.
heterodimers and inhibits downstream signaling as well as Cetuximab is an mAb that treats metastatic colorectal
antibody-dependent cell cytotoxicity. The main reasons cancer and squamous cell cancer (head-and-neck squamous
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reported for resistance to trastuzumab in patients are cell cancer). The use of cetuximab and panitumumab in
decreased interactions with HER2 due to blockage by cell- colorectal cancer patients is successful. 171,172 However,
surface proteins like mucin-4. Consistent treatment with treatment with cetuximab and panitumumab as single
166
trastuzumab leads to decreased expression of the tumor agents was only 10% effective in clinical significance. This
suppressor PTEN gene and activation of the Akt signaling clearly explains the development of resistance to the therapy.
pathway. Another main reason for developing resistance Most patients develop resistance within 3–12 months
is the activation of the phosphatidylinositol 3-kinase/ of starting therapy. The most probable explanation for
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Akt pathway, which can lead to decreased sensitivity to developing resistance is, but not limited to, RAS mutations

Volume 2 Issue 3 (2025) 31 doi: 10.36922/IMO025200022