Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Takeuchi, Kenji; Ito, F.

doi:10.1248/bpb.34.1774

Cited by 141 publications

(114 citation statements)

References 90 publications

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“…(22). Abnormalities in tyrosine kinases play a role in the pathogenesis of numerous inherited or acquired human diseases from cancer to immune deficiencies (23,24). Enrichment of low-abundance tyrosine phosphorylated proteins is necessary for a successful comprehensive LC-MS/MS analysis.…”

mentioning

confidence: 99%

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Breitkopf

Yuan

Pihán

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Hypothesis directed proteomics offers higher throughput over global analyses. We show that immunoprecipitation (IP)-tandem mass spectrometry (LC-MS/MS) in H929 multiple myeloma (MM) cancer cells led to the discovery of a rare and unexpected BCR-ABL fusion, informing a therapeutic intervention using imatinib (Gleevec). BCR-ABL is the driving mutation in chronic myeloid leukemia (CML) and is uncommon to other cancers. Three different IP-MS experiments central to cell signaling pathways were sufficient to discover a BCR-ABL fusion in H929 cells: phosphotyrosine (pY) peptide IP, p85 regulatory subunit of phosphoinositide-3-kinase (PI3K) IP, and the GRB2 adaptor IP. The pY peptides inform tyrosine kinase activity, p85 IP informs the activating adaptors and receptor tyrosine kinases (RTKs) involved in AKT activation and GRB2 IP identifies RTKs and adaptors leading to ERK activation. Integration of the bait-prey data from the three separate experiments identified the BCR-ABL protein complex, which was confirmed by biochemistry, cytogenetic methods, and DNA sequencing revealed the e14a2 fusion transcript. The tyrosine phosphatase SHP2 and the GAB2 adaptor protein, important for MAPK signaling, were common to all three IP-MS experiments. The comparative treatment of tyrosine kinase inhibitor (TKI) drugs revealed only imatinib, the standard of care in CML, was inhibitory to BCR-ABL leading to down-regulation of pERK and pS6K and inhibiting cell proliferation. These data suggest a model for directed proteomics from patient tumor samples for selecting the appropriate TKI drug(s) based on IP and LC-MS/MS. The data also suggest that MM patients, in addition to CML patients, may benefit from BCR-ABL diagnostic screening.targeted therapies | personalized medicine | protein-protein interactions P roteomics studies over the last decade have provided significant advancements in our understanding of the functional landscape of proteins, their posttranslational modifications and the protein-protein interactions (PPI) (1-3). This is especially important for diseases such as cancer because proteins and their transient posttranslational modifications (PTMs) reflect the changes cells undergo during pathogenic development. Modern high-resolution mass spectrometers are well suited for these analyses and have led the efforts in this field of proteomics, allowing researchers to analyze dynamic changes in cell lines or tissue and to distinguish between normal and unhealthy states (4, 5). PPI networks and phosphoproteomics are important for understanding the function and regulation of pathways leading to cell growth and proliferation in diseases such as cancer. The advantage of analyzing purified protein complexes is the ability to identify specific interacting proteins and posttranslational modifications that may otherwise go undetected in large-scale global analyses. This can be achieved by performing an immunoprecipitation (IP) with a bait protein and analyzing the prey proteins using microcapillary-tandem mass spectrometry (LC-MS/MS) (6-1...

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mentioning

confidence: 99%

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Breitkopf

Yuan

Pihán

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…EGFRs (EGFR/HER1/ErbB1, EGFR2/HER2/ ErbB2, EGFR3/HER3/ErbB3), VEGFR, platelet-derived growth factor receptor (PDGFR), hepatocyte growth factor receptor (HGFR), RET, insulin-like growth factor receptor (IGFR), and fibroblast growth factor receptor (FGFR) are classes of receptor tyrosine kinases that are usually constitutively active in most cancers and inhibition of these kinases using small molecule inhibitors has been found to sensitize the tumor cells to apoptosis [11]. Small molecule inhibitors of IGF-1R can be used to block IGF-1R function.…”

Section: Small Molecule Kinase Inhibitorsmentioning

confidence: 99%

Untitled

2014

Integr Cancer Sci Therap

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Cancer is one of the major health problems with a high mortality rate. Apart from the genetic changes in cancer cells, epigenetic and environmental factors play an important role towards the progression of tumor. The new cancer cases worldwide are estimated to increase to 19.3 million per year by 2025, due to the changing lifestyle and increase in longevity. Social and economic changes have contributed to rising risks of cancers associated with dietary and hormonal factors. Although traditional therapies have been effective in cancer treatment, they often have adverse side effects due to their non specific action on both normal and tumor cells. Therefore, targeted treatment strategies using small molecule inhibitors are being extensively studied. These compounds are usually ≤500Da size and are often administered orally. Their small size also allows them to translocate through the plasma membrane and interact with the cytoplasmic domain of cell-surface receptors and intracellular signaling molecules. In principle, small molecule compounds can be developed to target any portion of a molecule, regardless of the target's cellular location. In this review, we provide a summary of the small molecule inhibitors (SMIs) used in the cancer therapy, and elaborate on the recent advances in cancer therapies with emphasis on SMIs that block the growth of cancer cells.

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“…Erlotinib is used for the treatment of pancreatic carcinomas and NSCLC, while gefitinib is used for the treatment of NSCLC (9). A number of TKIs targeting several cancers have been approved for clinical use, and numerous newly developed TKIs are currently undergoing clinical trials (17).…”

Section: Tyrosine Kinase Inhibitors (Tkis)mentioning

confidence: 99%

Molecular mechanisms of lung-specific toxicity induced by epidermal growth factor receptor tyrosine kinase inhibitors

Sakao

2012

Oncology Letters

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Abstract. Lung-specific toxicity induced by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for the treatment of non-small cell lung cancer (NSCLC) has emerged as a critical side-effect. Although the clinical features of the pulmonary side-effects of TKIs have been characterized, the details of the molecular mechanisms in the development of this lung-specific toxicity remain to be elucidated. EGFR-dependent epithelial regeneration and restoration plays an important role in the recovery process from lung injury. The lung comprises a unique environment where epithelial cells are exposed to internal agents in the systemic circulation and to airborne particles through the mouth and nose. This unique environment may also be associated with the development of lung-specific toxicity induced by EGFR-TKIs. Therefore, the aim of this review was to provide further insight into the molecular mechanisms of lung-specific toxicity in the context of treatment with EGFR-TKIs.

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Receptor Tyrosine Kinases and Targeted Cancer Therapeutics

Cited by 141 publications

References 90 publications

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Detection of a rare BCR–ABL tyrosine kinase fusion protein in H929 multiple myeloma cells using immunoprecipitation (IP)-tandem mass spectrometry (MS/MS)

Untitled

Molecular mechanisms of lung-specific toxicity induced by epidermal growth factor receptor tyrosine kinase inhibitors

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