Receptor tyrosine kinases regulate signal transduction through a liquid-liquid phase separated state.

The recruitment of signaling proteins into activated receptor tyrosine kinases (RTKs) to produce rapid, high-fidelity downstream response is exposed to the ambiguity of random diffusion to the target site. Liquid-liquid phase separation (LLPS) overcomes this by providing elevated, localized concentrations of the required proteins while impeding competitor ligands. Here, we show a subset of phosphorylation-dependent RTK-mediated LLPS states. We then investigate the formation of phase-separated droplets comprising a ternary complex including the RTK, (FGFR2); the phosphatase, SHP2; and the phospholipase, PLCγ1, which assembles in response to receptor phosphorylation. SHP2 and activated PLCγ1 interact through their tandem SH2 domains via a previously undescribed interface. The complex of FGFR2 and SHP2 combines kinase and phosphatase activities to control the phosphorylation state of the assembly while providing a scaffold for active PLCγ1 to facilitate access to its plasma membrane substrate. Thus, LLPS modulates RTK signaling, with potential consequences for therapeutic intervention.

Exploring the potential of EphA2 receptor signaling pathway: a comprehensive review in cancer treatment.

The protein encoded by the ephrin type-A receptor 2 (EphA2) gene is a member of the ephrin receptor subfamily of the receptor tyrosine kinase family (RTKs). Eph receptors play a significant role in various biological processes, particularly cancer progression, development, and pathogenesis. They have been observed to regulate cancer cell growth, migration, invasion, tumor development, invasiveness, angiogenesis, and metastasis. To target EphA2 activity, various molecular, genetic, biochemical, and pharmacological strategies have been extensively tested in laboratory cultures and animal models. Notably, drugs, such as dasatinib, initially designed to target the kinase family, have demonstrated an additional capability to target EphA2 activity. Additionally, a novel monoclonal antibody named EA5 has emerged as a promising option to counteract the effects of EphA2 overexpression and restore tamoxifen sensitivity in EphA2-transfected MCF-7 cells during in vitro experiments. This antibody mimicked the binding of Ephrin A to EphA2. These methods offer potential avenues for inhibiting EphA2 activity, which could significantly decelerate breast cancer progression and restore sensitivity to certain drugs. This review article comprehensively covers EphA2's involvement in multiple malignancies, including ovarian, colorectal, breast, lung, glioma, and melanoma. Furthermore, we discuss the structure of EphA2, the Eph-Ephrin signaling pathway, various EphA2 inhibitors, and the mechanisms of EphA2 degradation. This article provides an extensive overview of EphA2's vital role in different types of cancers and outlines potential therapeutic approaches to target EphA2, shedding light on the underlying molecular mechanisms that make it an attractive target for cancer treatment.

New antiproliferative 3-substituted oxindoles inhibiting EGFR/VEGFR-2 and tubulin polymerization.

New 3-substituted oxindole derivatives were designed and synthesized as antiproliferative agents. The antiproliferative activity of compounds 6a-j was evaluated against 60 NCI cell lines. Among these tested compounds, compounds 6f and 6g showed remarkable antiproliferative activity, specifically against leukemia and breast cancer cell lines. Compound 6f was the most promising antiproliferative agent against MCF-7 (human breast cancer) with an IC50 value of 14.77 µM compared to 5-fluorouracil (5FU) (IC50 = 2.02 µM). Notably, compound 6f hampered receptor tyrosine EGFR fundamentally with an IC50 value of 1.38 µM, compared to the reference sunitinib with an IC50 value of 0.08 µM. Moreover, compound 6f afforded anti-tubulin polymerization activity with an IC50 value of 7.99 µM as an outstanding observable activity compared with the reference combretastatin A4 with an IC50 value of 2.64 µM. In silico molecular-docking results of compound 6f in the ATP-binding site of EGFR agreed with the in vitro results. Besides, the investigation of the physicochemical properties of compound 6f via the egg-boiled method clarified good lipophilicity, GIT absorption, and blood-brain barrier penetration properties.

The SCF/KIT axis in human mast cells: Capicua acts as potent KIT repressor and ERK predominates PI3K.

BACKGROUND: The SCF/KIT axis regulates nearly all aspects of mast cell (MC) biology. A comprehensive view of SCF-triggered phosphorylation dynamics is lacking. The relationship between signaling modules and SCF-supported functions likewise remains ill-defined. METHODS: Mast cells were isolated from human skin; upon stimulation by SCF, global phosphoproteomic changes were analyzed by LC-MS/MS and selectively validated by immunoblotting. MC survival was inspected by YoPro; BrdU incorporation served to monitor proliferation. Gene expression was quantified by RT-qPCR and cytokines by ELISA. Pharmacological inhibitors were supplemented by ERK1 and/or ERK2 knockdown. CIC translocation and degradation were studied in nuclear and cytoplasmic fractions. CIC's impact on KIT signaling and function was assessed following RNA interference. RESULTS: ≈5400 out of ≈10,500 phosphosites experienced regulation by SCF. The MEK/ERK cascade was strongly induced surpassing STAT5 > PI3K/Akt > p38 > JNK. Comparison between MEK/ERK's and PI3K's support of basic programs (apoptosis, proliferation) revealed equipotency between modules. In functional outputs (gene expression, cytokines), ERK was the most influential kinase. OSM and LIF production was identified in skin MCs. Strikingly, SCF triggered massive phosphorylation of a protein not associated with KIT previously: CIC. Phosphorylation was followed by CIC's cytoplasmic appearance and degradation, the latter sensitive to protease but not preoteasome inhibition. Both shuttling and degradation were ERK-dependent. Conversely, CIC-siRNA facilitated KIT signaling, functional outputs, and survival. CONCLUSION: The SCF/KIT axis shows notable strength in MCs, and MEK/ERK as most prominent module. An inhibitory circuit exists between KIT and CIC. CIC stabilization in MCs may turn out as a therapeutic option to interfere with allergic and MC-driven diseases.

Discovery of new symmetrical and asymmetrical nitrile-containing 1,4-dihydropyridine derivatives as dual kinases and P-glycoprotein inhibitors: synthesis, in vitro assays, and in silico studies.

Two new series of symmetric (1a-h) and asymmetric (2a-l) 1,4-DHP derivatives were designed, synthesised, and evaluated as anticancer agents. In vitro anticancer screening of target compounds via National cancer institute "NCI" revealed that analogues 1g, 2e, and 2l demonstrated antiproliferative action with mean growth inhibition percentage "GI%" = 41, 28, and 64, respectively. The reversal doxorubicin (DOX) effects of compounds 1g, 2e, and 2l were examined and illustrated better cytotoxic activity with IC50 =1.12, 3.64, and 3.57 µM, respectively. The most active anticancer analogues, 1g, 2e, and 2l, were inspected for their putative mechanism of action by estimating their epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2), and Bruton's tyrosine kinase (BTK) inhibitory activities. Furthermore, the antimicrobial activity of target compounds was assessed against six different pathogens, followed by determining the minimum inhibitory concentration "MIC" values for the most active analogues. Molecular docking study was achieved to understand mode of interactions between selected inhibitors and different biological targets.

Crystal structure of clinically reported mutations Gly656Arg, Gly656Glu and Asp751His identified in the kinase domain of EphA7.

Erythropoietin producing hepatocellular (Eph) forms the largest family of receptor tyrosine kinases (RTK). As a family, Eph regulates physiological events such as cell-cell interaction, cell migration, and adhesion. The Kinase domain is the catalytic core of the Eph receptor and is highly conserved sequentially. EphA7 has been recently regarded as a cancer driver gene and comprises several clinically important mutations. Three of the EphA7 mutations Gly656Glu, Gly656Arg, and Asp751His, present in the kinase domain, are predicted to be highly pathogenic. Furthermore, Gly656Glu and Gly656Arg are reported to be hotspot mutations. Considering the importance of mutations, crystals structure of EphA7 Gly656Glu, Gly656Arg, and Asp751His mutants has been explored. Changes in folding pattern and intramolecular interactions were observed in mutant structures. Secondary structural changes were observed in the hinge region of EphA7 Gly656Arg and Asp751His structure, affecting the transition of kinase domain between open and closed conformations. EphA7 Asp751His mutant structure shows a distorted nucleotide-binding groove. Differences were observed in hydrogen bonding and hydrophobic interactions between the catalytic and highly conserved DFG motif in the EphA7 mutants, which may influence the catalytic activity of kinase domain.

Neuregulin Signaling in the Tumor Microenvironment.

Neuregulins, members of the largest subclass of growth factors of the epidermal growth factor family, mediate a myriad of cellular functions including survival, proliferation, and differentiation in normal tissues through binding to receptor tyrosine kinases of the ErbB family. However, aberrant neuregulin signaling in the tumor microenvironment is increasingly recognized as a key player in initiation and malignant progression of human cancers. In this chapter, we focus on the role of neuregulin signaling in the hallmarks of cancer, including cancer initiation and development, metastasis, as well as therapeutic resistance. Moreover, role of neuregulin signaling in the regulation of tumor microenvironment and targeting of neuregulin signaling in cancer from the therapeutic perspective are also briefly discussed.

Targeting RTK-PI3K-mTOR Axis in Gliomas: An Update.

Gliomas are the most common and challenging malignancies of the central nervous system (CNS), due to their infiltrative nature, tendency to recurrence, and poor response to treatments. Indeed, despite the advances in neurosurgical techniques and in radiation therapy, the modest effects of therapy are still challenging. Moreover, tumor recurrence is associated with the onset of therapy resistance; it is therefore critical to identify effective and well-tolerated pharmacological approaches capable of inducing durable responses in the appropriate patient groups. Molecular alterations of the RTK/PI3K/Akt/mTOR signaling pathway are typical hallmarks of glioma, and several clinical trials targeting one or more players of this axis have been launched, showing disappointing results so far, due to the scarce BBB permeability of certain compounds or to the occurrence of resistance/tolerance mechanisms. However, as RTK/PI3K/mTOR is one of the pivotal pathways regulating cell growth and survival in cancer biology, targeting still remains a strong rationale for developing strategies against gliomas. Future rigorous clinical studies, aimed at addressing the tumor heterogeneity, the interaction with the microenvironment, as well as diverse posology adjustments, are needed-which might unravel the therapeutic efficacy and response prediction of an RTK/PI3K/mTOR-based approach.

All Good Things Must End: Termination of Receptor Tyrosine Kinase Signal.

Receptor tyrosine kinases (RTKs) are membrane receptors that regulate many fundamental cellular processes. A tight regulation of RTK signaling is fundamental for development and survival, and an altered signaling by RTKs can cause cancer. RTKs are localized at the plasma membrane (PM) and the major regulatory mechanism of signaling of RTKs is their endocytosis and degradation. In fact, RTKs at the cell surface bind ligands with their extracellular domain, become active, and are rapidly internalized where the temporal extent of signaling, attenuation, and downregulation are modulated. However, other mechanisms of signal attenuation and termination are known. Indeed, inhibition of RTKs' activity may occur through the modulation of the phosphorylation state of RTKs and the interaction with specific proteins, whereas antagonist ligands can inhibit the biological responses mediated by the receptor. Another mechanism concerns the expression of endogenous inactive receptor variants that are deficient in RTK activity and take part to inactive heterodimers or hetero-oligomers. The downregulation of RTK signals is fundamental for several cellular functions and the homeostasis of the cell. Here, we will review the mechanisms of signal attenuation and termination of RTKs, focusing on FGFRs.

Structural and Functional Insights into the Transmembrane Domain Association of Eph Receptors.

Eph receptors are the largest family of receptor tyrosine kinases and by interactions with ephrin ligands mediate a myriad of processes from embryonic development to adult tissue homeostasis. The interaction of Eph receptors, especially at their transmembrane (TM) domains is key to understanding their mechanism of signal transduction across cellular membranes. We review the structural and functional aspects of EphA1/A2 association and the techniques used to investigate their TM domains: NMR, molecular modelling/dynamics simulations and fluorescence. We also introduce transmembrane peptides, which can be used to alter Eph receptor signaling and we provide a perspective for future studies.

The Ephb2 Receptor Uses Homotypic, Head-to-Tail Interactions within Its Ectodomain as an Autoinhibitory Control Mechanism.

The Eph receptor tyrosine kinases and their ephrin ligands direct axon pathfinding and neuronal cell migration, as well as mediate many other cell-cell communication events. Their dysfunctional signaling has been shown to lead to various diseases, including cancer. The Ephs and ephrins both localize to the plasma membrane and, upon cell-cell contact, form extensive signaling assemblies at the contact sites. The Ephs and the ephrins are divided into A and B subclasses based on their sequence conservation and affinities for each other. The molecular details of Eph-ephrin recognition have been previously revealed and it has been documented that ephrin binding induces higher-order Eph assemblies, which are essential for full biological activity, via multiple, distinct Eph-Eph interfaces. One Eph-Eph interface type is characterized by a homotypic, head-to-tail interaction between the ligand-binding and the fibronectin domains of two adjacent Eph molecules. While the previous Eph ectodomain structural studies were focused on A class receptors, we now report the crystal structure of the full ectodomain of EphB2, revealing distinct and unique head-to-tail receptor-receptor interactions. The EphB2 structure and structure-based mutagenesis document that EphB2 uses the head-to-tail interactions as a novel autoinhibitory control mechanism for regulating downstream signaling and that these interactions can be modulated by posttranslational modifications.

Receptor tyrosine kinases in PI3K signaling: The therapeutic targets in cancer.

The phosphoinositide 3-kinase (PI3K) pathway, one of the most commonly activated signaling pathways in human cancers, plays a crucial role in the regulation of cell proliferation, differentiation, and survival. This pathway is usually activated by receptor tyrosine kinases (RTKs), whose constitutive and aberrant activation is via gain-of-function mutations, chromosomal rearrangement, gene amplification and autocrine. Blockage of PI3K pathway by targeted therapy on RTKs with tyrosine kinases inhibitors (TKIs) and monoclonal antibodies (mAbs) has achieved great progress in past decades; however, there still remain big challenges during their clinical application. In this review, we provide an overview about the most frequently encountered alterations in RTKs and focus on current therapeutic agents developed to counteract their aberrant functions, accompanied with discussions of two major challenges to the RTKs-targeted therapy in cancer - resistance and toxicity.

Proproliferative function of adaptor protein GRB10 in prostate carcinoma.

Growth factor receptor-binding protein 10 (GRB10) is a well-known adaptor protein and a recently identified substrate of the mammalian target of rapamycin (mTOR). Depletion of GRB10 increases insulin sensitivity and overexpression suppresses PI3K/Akt signaling. Because the major reason for the limited efficacy of PI3K/Akt-targeted therapies in prostate cancer (PCa) is loss of mTOR-regulated feedback suppression, it is therefore important to assess the functional importance and regulation of GRB10 under these conditions. On the basis of these background observations, we explored the status and functional impact of GRB10 in PCa and found maximum expression in phosphatase and tensin homolog (PTEN)-deficient PCa. In human PCa samples, GRB10 inversely correlated with PTEN and positively correlated with pAKT levels. Knockdown of GRB10 in nontumorigenic PTEN null mouse embryonic fibroblasts and tumorigenic PCa cell lines reduced Akt phosphorylation and selectively activated a panel of receptor tyrosine kinases. Similarly, overexpression of GRB10 in PTEN wild-type PCa cell lines accelerated tumorigenesis and induced Akt phosphorylation. In PTEN wild-type PCa, GRB10 overexpression promoted mediated PTEN interaction and degradation. PI3K (but not mTOR) inhibitors reduced GRB10 expression, suggesting primarily PI3K-driven regulation of GRB10. In summary, our results suggest that GRB10 acts as a major downstream effector of PI3K and has tumor-promoting effects in prostate cancer.-Khan, M. I., Al Johani, A., Hamid, A., Ateeq, B., Manzar, N., Adhami, V. M., Lall, R. K., Rath, S., Sechi, M., Siddiqui, I. A., Choudhry, H., Zamzami, M. A., Havighurst, T. C., Huang, W., Ntambi, J. M., Mukhtar, H. Proproliferatve function of adaptor protein GRB10 in prostate carcinoma.

Liraglutide attenuates gefitinib-induced cardiotoxicity and promotes cardioprotection through the regulation of MAPK/NF-κB signaling pathways.

Gefitinib is an effective treatment for patients with locally advanced non-small cell lung cancer. However, it is associated with cardiotoxicity that can limit its clinical use. Liraglutide, a glucagon-like peptide 1 receptor agonist, showed potent cardioprotective effects with the mechanism is yet to be elucidated. Therefore, this study aimed to determine the efficiency of liraglutide in protecting the heart from damage induced by gefitinib. Adult male Wistar rats were randomly divided into control group, liraglutide group (200 µg/kg by i.p. injection), gefitinib group (30 mg/kg orally) and liraglutide plus gefitinib group. After 28 days, blood and tissue samples were collected for histopathological, biochemical, gene and protein analysis. We demonstrated that gefitinib treatment (30 mg/kg) resulted in cardiac damage as evidenced by histopathological studies. Furthermore, serum Creatine kinase-MB (CK-MB), N-terminal pro B-type natriuretic peptide (NT-proBNP) and cardiac Troponin-I (cTnI) were markedly elevated in gefitinib group. Pretreatment with liraglutide (200 µg/kg), however, restored the elevation in serum markers and diminished gefitinib-induced cardiac damage. Moreover, liraglutide improved the gene and protein levels of anti-oxidant (superoxide dismutase) and decreased the oxidative stress marker (NF-κB). Mechanistically, liraglutide offered protection through upregulation of the survival kinases (ERK1/2 and Akt) and downregulation of stress-activated kinases (JNK and P38). In this study, we provide evidence that liraglutide protects the heart from gefitinib-induced cardiac damage through its anti-oxidant property and through the activation of survival kinases.

Receptor tyrosine kinase targeting in glioblastoma: performance, limitations and future approaches.

From all central nervous system tumors, gliomas are the most common. Nowadays, researchers are looking for more efficient treatments for these tumors, as well as ways for early diagnosis. Receptor tyrosine kinases (RTKs) are major targets for oncology and the development of small-molecule RTK inhibitors has been proven successful in cancer treatment. Mutations or aberrant activation of the RTKs and their intracellular signaling pathways are linked to several malignant diseases, including glioblastoma. The progress in the understanding of malignant glioma evolution has led to RTK targeted therapies with high capacity to improve the therapeutic response while reducing toxicity. In this review, we present the most important RTKs (i.e. EGFR, IGFR, PDGFR and VEGFR) currently used for developing cancer therapeutics together with the potential of RTK-related drugs in glioblastoma treatment. Also, we focus on some therapeutic agents that are currently at different stages of research or even in clinical phases and proved to be suitable as re-purposing candidates for glioblastoma treatment.

Activation and function of receptor tyrosine kinases in human clear cell renal cell carcinomas.

BACKGROUND: The receptor tyrosine kinases (RTKs) play critical roles in the development of cancers. Clear cell renal cell carcinoma (ccRCC) accounts for 75% of the RCC. The previous studies on the RTKs in ccRCCs mainly focused on their gene expressions. The activation and function of the RTKs in ccRCC have not been fully investigated. METHODS: In the present study, we analyzed the phosphorylation patterns of RTKs in human ccRCC patient samples, human ccRCC and papillary RCC cell lines, and other kidney tumor samples using human phospho-RTK arrays. We further established ccRCC patient-derived xenograft models in nude mice and assessed the effects of RTKIs (RTK Inhibitors) on the growth of these cancer cells. Immunofluorescence staining was used to detect the localization of keratin, vimentin and PDGFRß in ccRCCs. RESULTS: We found that the RTK phosphorylation patterns of the ccRCC samples were all very similar, but different from that of the cell lines, other kidney tumor samples, as well as the adjacent normal tissues. 9 RTKs, EGFR1-3, Insulin R, PDGFRß, VEGFR1, VEGFR2, HGFR and M-CSFR were found to be phosphorylated in the ccRCC samples. The adjacent normal tissues, on the other hand, had predominantly only two of the 4 EGFR family members, EGFR and ErbB4, phosphorylated. What's more, the RTK phosphorylation pattern of the xenograft, however, was different from that of the primary tissue samples. Treatment of the xenograft nude mice with corresponding RTK inhibitors effectively inhibited the Erk1/2 signaling pathway as well as the growth of the tumors. In addition, histological staining of the cancer samples revealed that most of the PDGFRß expressing cells were localized in the vimentin-positive periepithelial stroma. CONCLUSIONS: Overall, we have identified a set of RTKs that are characteristically phosphorylated in ccRCCs. The phosphorylation of RTKs in ccRCCs were determined by the growing environments. These phosphorylated/activated RTKs will guide targeting drugs development of more effective therapies in ccRCCs. The synergistical inhibition of RTKIs combination on the ccRCC suggest a novel strategy to use a combination of RTKIs to treat ccRCCs.

Receptor tyrosine kinases (RTKs) consociate in regulatory clusters in Alzheimer's disease and type 2 diabetes.

Alzheimer's disease (AD) and type 2 diabetes (T2D) share the common hallmark of insulin resistance. It is conjectured that receptor tyrosine kinases (RTKs) play definitive roles in the process. To decipher the signaling overlap behind this phenotypic resemblance, the activity status of RTKs is probed in post-mortem AD and T2D tissues and cell models. Activities of only about one-third changed in a similar fashion, whereas about half of them showed opposite outcomes when exposed to contrasting signals akin to AD and T2D. Interestingly, irrespective of disease type, RTKs with enhanced and compromised activities clustered distinctly, indicating separate levels of regulations. Similar regulatory mechanisms within an activity cluster could be inferred, which have potential to impact future therapeutic developments.

Novel promising 4-anilinoquinazoline-based derivatives as multi-target RTKs inhibitors: Design, molecular docking, synthesis, and antitumor activities in vitro and vivo.

4-Anilinoquinazoline derivatives function as tyrosine kinase inhibitors (TKIs). Novel TKIs are needed for cancer mutations and drug-resistant cells. We designed and synthesized 4-anilinoquinazoline derivatives with substitutions at quinazoline positions 6, 7 and 4 using a binding model with multi-target receptor tyrosine kinases, and assessed their antitumor activity against five human tumor cell lines (HepG2, A549, MCF-7, DU145, SH-SY5Y). The majority of the compounds inhibited the proliferation of all the cancer cell types, with some compounds displaying selective inhibition. Compounds 21, 25, 27, and 37 displayed IC50 values of 7.588, 8.619, 6.936, and 8.516 µM, respectively, for A549 cells, which were much lower than that of Gefitinib (14.803 µM). Compound 32 displayed an IC50 value of 2.756 µM for DU145 cells. The representative compound 40 had unexceptionable broad-spectrum inhibition for all cancer cell types, and demonstrate inhibition of vascular endothelial growth factor receptor 2 (VEGFR-2), platelet-derived growth factor receptor beta (PDGFR-ß), and epidermal growth factor receptor (EGFR) with IC50 values of 46.4, 673.6 and 384.8 nM, respectively, which were similar to those of Sorafenib for VEGFR-2 and PDGFR-ß (140.6 and 582.7 nM, respectively). Molecular docking results supported the molecular level assay results. Data for production of reactive oxygen species and assessment of matrix metalloproteinase corroborated the strong anti-proliferative effect of compound 40. The compound also displayed robust antitumor efficacy and relativity lower toxicity in a xenograft model. These attributes were similar to those of Sorafenib. Compound 40 drug warrants further study as a candidate.

Funerals and Feasts: The Immunological Rites of Cell Death.

The immune system functions as a vanguard against pathogens and toxins. While it is mostly considered to be activated on the basis of self versus non-self recognition, injury/infection and damage are unavoidably associated with cell death. Does cell death play a role in the regulation of the immune response? Cell death, for better or for worse, is an omnipresent process in all stages of life that are observed throughout most tissues in multicellular organisms. From development to homeostasis in adult organisms, cells commit to scheduled death, while cases of injury and infection result in unscheduled cell death. Novel understanding of the molecular mechanisms that govern cell death demonstrate that, in fact, a plethora of molecular processes participate in directed dying. Parallel to the molecular modalities directing cell death are machineries employed by the organism to respond to dying cells, including either eliciting an inflammatory or immunological response or altogether avoiding it. Disturbing the careful coupling of these two processes is often met with pathology - on one hand a failure to respond to cell death may contribute to the lack of proper immune response or defective development, and on the other hand exaggerated or aberrant response to cell death can trigger unregulated inflammation, autoimmunity, or fibrosis/scarring. Here we review the molecular mechanisms and associated effector responses that accompany some of the most well-known cell death modalities - with an emphasis on efferocytosis, a process by which the dead cell is recognized and engulfed. In doing so, we highlight the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases (RTKs) that functions dually in the recognition and engulfment of dead cells, and as an important negative regulator of inflammation.

EGFR-TKIs resistance via EGFR-independent signaling pathways.

Tyrosine kinase inhibitors (TKIs)-treatments bring significant benefit for patients harboring epidermal growth factor receptor (EGFR) mutations, especially for those with lung cancer. Unfortunately, the majority of these patients ultimately develop to the acquired resistance after a period of treatment. Two central mechanisms are involved in the resistant process: EGFR secondary mutations and bypass signaling activations. In an EGFR-dependent manner, acquired mutations, such as T790 M, interferes the interaction between TKIs and the kinase domain of EGFR. While in an EGFR-independent manner, dysregulation of other receptor tyrosine kinases (RTKs) or abnormal activation of downstream compounds both have compensatory functions against the inhibition of EGFR through triggering phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK) signaling axes. Nowadays, many clinical trials aiming to overcome and prevent TKIs resistance in various cancers are ongoing or completed. EGFR-TKIs in accompany with the targeted agents for resistance-related factors afford a promising first-line strategy to further clinical application.