Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches

Saraon, Punit; Pathmanathan, Shivanthy; Snider, Jamie; Lyakisheva, Anna; Wong, Victoria; Štagljar, Igor

doi:10.1038/s41388-021-01841-2

Cited by 104 publications

(82 citation statements)

References 111 publications

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“…Tyrosine phosphorylation of SHP2 at Y452 and Y580 occurs downstream of RTK signaling [32,33]. Gene amplification of RTK causes overexpression and clustering of RTK, resulting in constitutive kinase activation and oncogenic signals [7]. Consistently, we observed that Y452 and Y580 of SHP2 were highly phosphorylated in DGC cell lines with Met or FGFR2 gene amplification, and the phosphorylation was dependent on Met or FGFR2 activity.…”

Section: Discussionsupporting

confidence: 79%

“…Acquired drug resistance is a major issue in targeted cancer therapy. The molecular mechanisms underlying resistance to RTK inhibitor include resistance mutations in RTK and activation of alternate RTKs [7]. In addition, adaptive resistance to MEK/ERK pathway inhibitors often occurs via RTK activation [58,59].…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant and oncogenic activation of receptor tyrosine kinases (RTKs) is frequently observed in a diverse range of carcinomas [7]. In the case of DGC, gene amplification of MET and FGFR2 has been reported [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling

Nagamura

Miyazaki

Nagano

et al. 2021

Cancers

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Diffuse-type gastric carcinoma (DGC) exhibits aggressive progression associated with rapid infiltrative growth, massive fibrosis, and peritoneal dissemination. Gene amplification of Met and fibroblast growth factor receptor 2 (FGFR2) receptor tyrosine kinases (RTKs) has been observed in DGC. However, the signaling pathways that promote DGC progression downstream of these RTKs remain to be fully elucidated. We previously identified an oncogenic tyrosine phosphatase, SHP2, using phospho-proteomic analysis of DGC cells with Met gene amplification. In this study, we characterized SHP2 in the progression of DGC and assessed the therapeutic potential of targeting SHP2. Although SHP2 was expressed in all gastric carcinoma cell lines examined, its tyrosine phosphorylation preferentially occurred in several DGC cell lines with Met or FGFR2 gene amplification. Met or FGFR inhibitor treatment or knockdown markedly reduced SHP2 tyrosine phosphorylation. Knockdown or pharmacological inhibition of SHP2 selectively suppressed the growth of DGC cells addicted to Met or FGFR2, even when they acquired resistance to Met inhibitors. Moreover, SHP2 knockdown or pharmacological inhibition blocked the migration and invasion of Met-addicted DGC cells in vitro and their peritoneal dissemination in a mouse xenograft model. These results indicate that SHP2 is a critical regulator of the malignant progression of RTK-addicted DGC and may be a therapeutic target.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

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SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling

Nagamura

Miyazaki

Nagano

et al. 2021

Cancers

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“…Receptor tyrosine kinases (RTKs) play an important role in tumor growth. 10 Platelet-derived growth factor receptor α (PDGFRα) and PDGFRβ have been found to be dysregulated as a result of loss of function of the TSC1-TSC2 complex. 11 , 12 To investigate whether the expression of other RTKs was changed upon loss of TSC2, RNA sequencing (RNA-seq) was performed to analyze differences in gene expression profiles between Tsc2 +/+ and Tsc2 −/− MEFs.…”

Section: Resultsmentioning

confidence: 99%

RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

Lin

Wan

Sun

et al. 2021

Molecular Therapy - Oncolytics

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“…Receptor tyrosine kinases (RTKs) are cell surface transmembrane proteins activated in response to ligand binding, an event conveying downstream stimulatory signals towards cell proliferation, migration, invasion, differentiation, and angiogenesis [149]. Aberrant RTK signaling, which may occur in response to genome amplification, gain of function mutations, or chromosome rearrangements, has been shown to contribute to tumor development and progression, as well as to anti-cancer treatment failure [149,150]. Most of the known human RTKs share a similar protein structure, with an extracellular ligand-binding (N)-terminal domain, a single spanning transmembrane helix, and an intracellular carboxyl(C)-terminal domain [151,152].…”

Section: Rtk Inhibitors (Rtkis)mentioning

confidence: 99%

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity

et al. 2022

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Mitochondria are key organelles for the maintenance of myocardial tissue homeostasis, playing a pivotal role in adenosine triphosphate (ATP) production, calcium signaling, redox homeostasis, and thermogenesis, as well as in the regulation of crucial pathways involved in cell survival. On this basis, it is not surprising that structural and functional impairments of mitochondria can lead to contractile dysfunction, and have been widely implicated in the onset of diverse cardiovascular diseases, including ischemic cardiomyopathy, heart failure, and stroke. Several studies support mitochondrial targets as major determinants of the cardiotoxic effects triggered by an increasing number of chemotherapeutic agents used for both solid and hematological tumors. Mitochondrial toxicity induced by such anticancer therapeutics is due to different mechanisms, generally altering the mitochondrial respiratory chain, energy production, and mitochondrial dynamics, or inducing mitochondrial oxidative/nitrative stress, eventually culminating in cell death. The present review summarizes key mitochondrial processes mediating the cardiotoxic effects of anti-neoplastic drugs, with a specific focus on anthracyclines (ANTs), receptor tyrosine kinase inhibitors (RTKIs) and proteasome inhibitors (PIs).

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Receptor tyrosine kinases and cancer: oncogenic mechanisms and therapeutic approaches

Cited by 104 publications

References 111 publications

SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling

SHP2 as a Potential Therapeutic Target in Diffuse-Type Gastric Carcinoma Addicted to Receptor Tyrosine Kinase Signaling

RUNX1/EGFR pathway contributes to STAT3 activation and tumor growth caused by hyperactivated mTORC1

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity

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