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

determination. In this structure, one KD (activator) activation in epidermal tumor cells. Recent publications
allosterically interacts with its partner (receiver) to support the activation of EGFR signaling pathways in
activate the EGFR. This dimerization interaction occurs epithelial cancers, including breast, ovarian, prostate, and
at the N-lobe of the receiver and the C-lobe of the non-small cell lung cancer (NSCLC). 116-118
activator, resembling the cyclin-mediated CDK type
of activation. Unlike other RTKs, the EGFR activation 4.2. Role of Src-tyrosine kinase in cancers
mechanism is driven by protein-protein interactions SFKs play a crucial role in various cellular processes, such
at the dimerization interface. This mechanism is also as cell proliferation, adhesion, and migration. Their
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observed in other members such as HER2, HER3, and dysregulation is frequently implicated in tumors, where
HER4 (Figure 2A and B). Further molecular dynamics they are often overexpressed due to their role in cell-cell
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simulation studies demonstrated how EGFR transitions adhesion. 119,120 Particularly, Src is involved in activating
between active and inactive conformations through local STAT transcription factors, promoting tumorigenesis, and
unfolding at the hinge region between N- and C-lobes. influencing cytokine signaling in hematopoietic cells. It
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Together, these structural insights have significant also plays a significant role in regulating the RAS/RAF/
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clinical implications, helping in developing novel targeted MEK/ERK MAPK and VEGF pathways in various tumors.
antibodies like erlotinib and lapatinib, which exploit In addition, Src plays a vital role in facilitating tumor cell
EGFR’s conformational flexibility. For example, EGFR invasion by phosphorylating target substrates, aiding in
inhibitor Mig6 is known to block the asymmetric dimer the translocation of tumor cells through matrix barriers
interface and inhibit activation. This understanding and tissue compartments. Invasion is a complex process,
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highlights the unique regulatory mechanism of EGFR and tumor Src activation leads to the phosphorylation
and its critical role in cancer biology. of targeted substrates, influencing the activity of cellular
proteins to carry out this entire cellular process. SFKs
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4. The role of TKs in cancers are activated in tumors through mutations of the Src
TKs, a large family of kinases that include both RTKs and allele, leading to a disorganized negative regulatory
NRTKs, serve as critical molecular switches in regulating pathway or by binding to activating partners such as
various cellular processes such as growth, survival, growth factors (Her 2/Neu, PDGF, EGFR). Oncogenic
development, and differentiation. Several studies have Src (v-Src) can activate Ras by recruiting the Grd 2/Sos
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highlighted the role of PTKs in various cancers and their complex, thereby stimulating Ras-mediated tumorigenic
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potential for drug discovery. The current review focuses on signals. Furthermore, p120RasGAP-mediated activation
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EGFR and Src’s role as therapeutic targets for developing of c-Src is important for Ras-induced tumor invasion.
treatments against cancer cell-specific pathways. The TME plays a crucial role in Src upregulation, leading
to enhanced Src activity during cancer progression. In
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4.1. Role of EFGR-tyrosine kinase in cancers addition, inhibitory phosphorylation of Tyr530 is mediated
by the kinase Csk, which acts as a crucial regulator of Src
The EGFR family regulates developmental, metabolic, and activity. Given the importance of Src/EGFR in tumor
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physiological processes. A key aspect of EGFR-driven progression, the review will explore tyrosine kinase
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cancers involves mutations in the tyrosine KD of the EGFR therapeutic targets and also provide insights into potential
gene (exon 18–21), categorized into three classes: class I strategies for overcoming therapeutic resistance.
(in-frame deletions in exon 19), class II (single-nucleotide
substitutions), and class III (in-frame duplications 5. TKs as therapeutic targets
and or insertions in exon 20). 109,110 Class I accounts for
approximately 44% of the activating EGFR-TK domain 5.1. Development of TKIs
mutations, including deletion at LRE (Leu-747 to Glu-749), Cancer cell survival in the TME is challenging and highly
while class II mutations contribute ~41%, often affecting influenced by external factors. Cancer treatment has
the KD C-helix. Class III mutations, constituting ~5%, are advanced in developing TKIs. Discovery and development
less frequent but still play a role in tumor progression. 103,111 of imatinib (Gleevec, Inc.,) as the first effective TKI to
Sigismund et al., in 2018, best characterized the function treat chronic myeloid leukemia established it as a tumor-
of EGFR in ligand-and kinase-dependent activation, targeted therapy that acts specifically against the BCR-ABL
also known as the canonical EGFR signaling pathway. fusion protein. Inhibitors such as sorafenib and sunitinib
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Several of these stress pathways are activated in cancer served as early examples of TKIs approved for solid tumors
cells to induce survival advantage as well as resistance to and renal cell carcinoma. Over the past 20 years, robust
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cancer therapy. 113,114 Casanova et al. demonstrated that and specific TKIs with single or multiple targets have
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EGFR signaling is responsible for the Ha-ras-dependent been identified, including EGFR, ROS1, VEGFR, MEK,

Volume 2 Issue 3 (2025) 28 doi: 10.36922/IMO025200022