Abstract
GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.
Highlights
In line with this finding, it has been proposed that EGFR inhibitor treatment regulates overall and disease-free survival of NSCLC patients with the EGFR mutation coexisting with the PIK3CA double mutation
The significant role of Receptor tyrosine kinases (RTKs) has been shown in the RTKs-PTEN-KRAS-MTOR and RTKsPTEN-PIK3CA-AKT1-KRAS mutational pathways and augment translation, proliferation, and survival of tumor cells (Figure 5A,B)
In RTK class II, insulin (IGF) associated receptor families play in diverse pathophysiological cascades that regulate propagation and trans-differentiation of a single cell [57,58]
Summary
RTKs are enzymes that play critical roles in most fundamental cell programs in normal cells, including cell proliferation, cell cycle, migration, metabolism, programmed cell death, survival, and differentiation [9] These RTKs catalyze the transfer of gamma-phosphate of ATP to tyrosine hydroxyl groups on target proteins. RTK associated signaling cascades are able to mediate dysregulated propagation of cells and contribute to sensitivity towards apoptotic stimuli, especially resistance against drugs [6]. In cancer cells, these cascades are epigenetically altered to provide selective advantage. Other RTKIs, such as trastuzumab, which targets the HER2/ErbB2 receptor, cetuximab, erlotinib, and gefitinib, which targets the EGFR, effectively impede cancer growth
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