Biological Pathway Reviews

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

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

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

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

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

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

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 

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

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

Programmed death-ligand 1 (PD-L1) is a 40kDa type 1 transmembrane protein that plays a key role in keeping the body’s immune responses in check, especially during cases of autoimmune disease and viral infection.¹ PD-L1 can be found on certain normal cells and in excessive amounts on some cancer cells. When PD-L1 binds to PD-1, a protein found on T-cells, it inhibits the T-cells from activating and killing cells comprising PD-L1, including cancer cells.² Immune checkpoint inhibitors bind to PD-L1 and keep it from binding to PD-1, thus releasing PD-L1’s hold on the immune system and allowing T-cells to freely kill cancer cells.