Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?

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.

Keywords: cancer; clinical trials; drug resistance; mutation; receptor tyrosine kinases; targeted therapy.

Figure 1

Depiction of the fundamental drug resistance pathways in cancer cells. Drug efflux mediated cellular programming as drug inactivation, multi-drug resistance, apoptosis suppression, changes in drug metabolism, epigenetic modifications, drug targets, accelerated DNA-repair, and target gene amplification by which cancer cells become resistant to various drugs.

Figure 2

Molecular structural feature of RTK. A receptor tyrosine kinase’s extracellular domain can bind particular ligands such as growth factors, whereas the intracellular domain is responsible for the kinase’s (auto)phosphorylation. The external and internal domains are separated by the transmembrane region which is fixed in the cell membrane. The ATP-binding cleft is located between the two lobes of the intracellular domain. A schematic depiction of the ATP binding cleft with its numerous regions is shown on the right side of the image. Type I and type II tyrosine kinase inhibitor binding sites have been shown in biochemical general structure model.

Figure 3

OncoPrint analysis showing a frequency of mutations in RTKs, and other oncodrivers which suggest a multi-genomic alteration event in various cancers. Among the main RTKs, KRAS, PTEN, BRAF, EGFR, and ERBBs were the most frequently mutated in malignancies.

Figure 4

RTKs involvement in the RAS carcinogenic pathway. (A,B): Most RTKs in different malignancies have undergone mutational alterations (data was retrieved from cBioPortal patient cancer databank). In each pathway, RTKs including other oncodrivers were highly mutated and modulated a number of oncogenic mechanisms which promote tumor initiation, invasiveness, and tumor burden spread in several cancers.

Figure 5

Mutation of RTKs caused mutation in KRAS, PIK3CA, BRAF, PTEN, and mTOR ablation that induced tumorigenesis. (A,B) Mutational changes occurred in most RTKs, including EGFR, ERBB3, MET, ALK, RET, and FGFRs, which involved diverse mediators that induced cell proliferation. Pathways retrieved from cBioPortal patient cancer databank. (C) Association of RTKs with their inhibitor and major GO were visualized by an abstracted network analysis.

Figure 5

Mutation of RTKs caused mutation in KRAS, PIK3CA, BRAF, PTEN, and mTOR ablation that induced tumorigenesis. (A,B) Mutational changes occurred in most RTKs, including EGFR, ERBB3, MET, ALK, RET, and FGFRs, which involved diverse mediators that induced cell proliferation. Pathways retrieved from cBioPortal patient cancer databank. (C) Association of RTKs with their inhibitor and major GO were visualized by an abstracted network analysis.

Figure 6

EGFR-erlotinib binding structure: Erlotinib binds at the gap between the EGFR kinase domain’s amino- and carboxy-terminal lobes (PDB: 1M14). (A,B) A stereo image of the inhibitor binding site and surrounding EGFRK/erlotinib residues. An H-bond from the Met769 amide nitrogen to erlotinib is indicated by a dashed line (It was procured from Stamos et al. [52]).

Figure 7

VEGF structure and interaction with its inhibitor pazopanib. (A) Structure of VEGF, (B) PDB: 1Y6A, (C) PDB: 1Y6B. These docked images were taken from Harris et al., 2005 [54] and 2008 [55].