Tyrosine kinases in nodal peripheral T-cell lymphomas

Abstract

Nodal peripheral T-cell lymphomas (PTCL) are uncommon and heterogeneous tumors characterized by a dismal prognosis. Targeted therapy has been proposed. However, reliable targets are mostly represented by a few surface antigens (e.g., CD52 and CD30), chemokine receptors (e.g., CCR4), and epigenetic gene expression regulation. In the last two decades, however, several studies have supported the idea that tyrosine kinase (TK) deregulation might be relevant for both the pathogenesis and treatment of PTCL. Indeed, they can be expressed or activated as a consequence of their involvement in genetic lesions, such as translocations, or by ligand overexpression. The most striking example is ALK in anaplastic large-cell lymphomas (ALCL). ALK activity is necessary to support cell proliferation and survival, and its inhibition leads to cell death. Notably, STAT3 was found to be the main downstream ALK effector. Other TKs are consistently expressed and active in PTCLs, such as PDGFRA, and members of the T-cell receptor signaling family, such as SYK. Notably, as in the case of ALK, STAT proteins have emerged as key downstream factors for most of the involved TK.

Evaluation of the Interactions of Cabozantinib with Topoisomerase Enzymes by in vitro Enzyme Activity Assays, and its Effects on Cancer Cell Proliferation

“…Among the highlights, it is noteworthy that combination treatments provide successful results. It is suggested that checkpoint inhibitors and epigenetic modifiers combined with TKI may show significant effectiveness in many types of cancer, including lymphoma cells [31,32]. For the targeted treatment of unresectable HCC, Lenvatinib, Cabozantinib, Ramucirumab and Regorafenib have been approved [33].…”

Diverse and reprogrammable mechanisms of malignant cell transformation in lymphocytes: pathogenetic insights and translational implications

“…While the establishment of an overt lymphoid malignancy is almost universally a stepwise process, lymphomas expressing anaplastic lymphoma kinase (ALK) and, seemingly, similarly powerful oncogenic kinases ( 35 – 37 ) are a notable exception ( Figure 2 ). ALK, typically expressed as the NPM1-ALK (NPM1::ALK) hybrid protein due to t(2;5) chromosomal translocation resulting in fusion of the involved genes, profoundly reprograms targeted CD4+ T cells by conferring upon these cells features required for a full-fledged malignant cell transformation ( 38 , 39 ).…”

“…These chromosome 6p25.3 rearrangements confer an overall better prognosis, according to some studies ( 48 , 49 ). In other ALK-negative ALCL cases, translocations and related persistent expression of genes encoding tyrosine kinases, to some degree functionally analogous to ALK, has been identified ( 36 , 37 , 48 ). While one of these ALK-like kinases ROS1, is structurally closely related to ALK, the other two:TYK2 and JAK2 are members of the JAK tyrosine kinase family.…”

“…While one of these ALK-like kinases ROS1, is structurally closely related to ALK, the other two:TYK2 and JAK2 are members of the JAK tyrosine kinase family. They all activate similar signaling pathways, foremost STAT3, considered the key transcriptional effector for these chimeric oncogenic kinases ( 37 ). Of note, systemic and cutaneous ALCL lacking any of these chromosomal translocations and the related constitutively active fusion kinases, frequently display activating point mutations of JAK1 , JAK3 , and/or STAT3 ( 37 ).…”

“…They all activate similar signaling pathways, foremost STAT3, considered the key transcriptional effector for these chimeric oncogenic kinases ( 37 ). Of note, systemic and cutaneous ALCL lacking any of these chromosomal translocations and the related constitutively active fusion kinases, frequently display activating point mutations of JAK1 , JAK3 , and/or STAT3 ( 37 ). Similar point mutations of these genes occur also in breast implant-associated ALCL ( 48 ).…”