Biological Pathway Reviews

The ubiquitin-proteasome system (UPS) is the essential system within the body to ensure elimination of misfolded proteins.1 Proteins which are to be degraded are tagged with polyubiquitin chains, which are recognized by 19S.1 This particle, 19S, along with the 20S proteasome core, form the 26S proteasome overall.1

One protein the 20S proteasome targets for degradation is p53, a tumor suppressor gene.2 When the 20S proteasome is not functioning correctly, there is an increase in p53 levels which can lead to mutated forms of p53 that can lead to a variety of cancers.2 Proteasome inhibitors (PI) work as cancer treatment by targeting proteasome activity by binding with the 20S proteasome to prevent protein degredation.2

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ALK is a tyrosine kinase receptor that resides on chromosome 2p23.

Chromosomal rearrangements resulting in fusion genes leads to ALK tyrosine kinase that promote cell survival by activating a signaling pathway or by inhibition of apoptosis, which leads to cell proliferation.1

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Tumor cells have many characteristics, including genomic instability and oncogene activation, which should lead to apoptosis.1 In a bid to survive, tumor cells may become dependent on the BCL-2 protein.2 Certain cancer cells will overexpress BCL-2, which in turn impedes apoptosis and facilitates tumor growth and resistance to chemotherapy.3 These malignant cells that depend on BCL-2 for survival are likely to be sensitive to BCL-2 modulation.4

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BCMA is a member of the tumor necrosis factor receptor family that is expressed on plasma cells and on late stage normal and malignant B-cells.1 BCMA binds to BAFF, activating the NF-kB and MAPK8/JNK signaling pathways, which leads to the proliferation and survival of plasma cells.2

BCMA can also bind to a proliferation-inducing ligand (APRIL), which is associated with B cell development. Both ligands are associated with the regulation of cell survival and growth.3

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Oncogenic mutations in BRAF genes activate the RAF/MEK/ERK pathway, resulting in increased cell proliferation and resistance to apoptosis.1 BRAF mutations have been identified in 7% to 8% of all cancers.2 V600E is the most common activating mutations in BRAF and is associated with more aggressive cancer and worse prognosis.1,3

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Bruton's tyrosine kinase (BTK), a non-receptor tyrosine kinase, plays an important role in B-cell receptor activation.1 BCR activation results in translocation and phosphorylation of BTK. When BTK is inducted it activates phospholipase C and calcium mobilization, which results in downstream events, including proliferation, maturation, differentiation, and survival.2

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CD19 antigen is a type I transmembrane glycoprotein that is expressed in normal and malignant B cells.1 It plays a role in B cell development and maturation by modulating B-cell receptor signaling during lymphopoiesis.2,3 CD-19 deficiency leads to an impaired humoral response, resulting in increased susceptibility to infection.1,3

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CD30, a member of the tumor necrosis factor receptor superfamily, is expressed on active B cells and T cells.1 Signal mediation by CD30 through TRAF2 and TRAF5 can activate the transcription factor NF-κB pathway, leading to a positive regulation of the apoptotic process.2 CD30 can also signal the MAPK pathways, resulting in the survival of neoplastic cells. A positive feedback loop between the MAPK pathway and a nuclear transcription factor plays a role in the upregulation of CD30.2 

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The growth-factor-receptor tyrosine kinase family includes EGFR (ErbB1, HER1), ErbB2 (HER2, neu in rodents), ErbB3 (HER3), and ErbB4 (HER4).1 Receptor overexpression and ligand-dependent and ligand-independent mechanisms can cause abnormal EGFR activation. When EGFR is overexpressed in contributes to tumorigenesis, driving aggressive cell growth.2 It is recognized as a biomarker of resistance in tumors.3

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By modulating critical gene expression, EZH2 promotes cell cycle progression, cell proliferation, differentiation, and apoptosis.1 EZH2 is overexpressed in several malignant tumors and recurrently mutated in other cancers.2 It provides a critical role in promoting tumor growth and metastasis and can be regulated through multiple pathways transcriptionally, post-transcriptionally, and post-translationally.2

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