Signaling Pathways in Lymphoma: Pathogenesis and Therapeutic Targets

Abstract

Lymphoma is the fifth most common cancer in the USA. Most lymphomas are classified as non-Hodgkin's lymphoma, and nearly 95% of these cancers are of B-cell origin. B-cell receptor (BCR) surface expression and BCR functional signaling are critical for survival and proliferation of both healthy B cells, as well as most B-lymphoma cells. Agents that inhibit various components of the BCR signaling pathway, as well as parallel signaling pathways, are currently in clinical trials for the treatment of various lymphoma subtypes, including those targeting isoforms of PI3K, mTOR and BTK. In this review, we describe the signaling pathways in healthy mature B cells, the aberrant signaling in lymphomatous B cells and the rationale for clinical trials of agents targeting these pathways as well as the results of clinical trials to date. We propose that the entry into a kinase inhibitor era of lymphoma therapy will be as transformative for our patients as the advent of the antibody or chemotherapy era before it.

Chimeric antigen receptor T cells for the treatment of lymphoma

“…It is also possible that while lymphomas are terminally differentiated tumors, leukemia has greater plasticity due to the tumor rising from less committed population of cells. Lymphomas have aberrant cell survival signal transduction pathways, including Bcl2, Bcl6, BRAF, TP53, NRAS, PI3K/AKT/mTOR signaling, BTK signaling, LYN/SYK signaling, JAK2/STAT, and PKCβ signaling pathways (96,97). Relapsed/refractory NHL cells resistant to apoptotic signals presented by native immune cells, and cytotoxic drugs, in addition to activation of prosurvival signaling, could also make lymphoma more resistant to CAR T cell therapy.…”

Molecular Management of Chronic Lymphocytic Leukemia: Towards a Chemotherapy-Free Approach

“…15,18 Pathobiological expression of the B-cell receptor (BCR) signaling can cause disease progression in the malignant B-cell neoplastic diseases. 19 Bruton's tyrosine kinase (BTK) has a pivotal role in the BCR signaling. Normal B lymphocytes receive signals from BCR that are triggered by binding of the BCR to an external antigen.…”

Ibrutinib: From Molecule to Medicine

“…49,50 Thus, MCL, the clinically aggressive and incurable B-cell malignancy, may respond to ibrutinib therapy. 1,3,22,24,44,49 The blockade of BTK activity by ibrutinib could attenuate BCR signaling and induces cell death in a wide variety of B-lymphoproliferative diseases. A moderate to strong BTK expression in MCL cases in comparison to benign lymphoid tissues has been shown.…”

“…Pathobiological expression of the B-cell receptor (BCR) signaling can cause disease progression in the malignant B-cell neoplastic diseases. 1 Bruton's tyrosine kinase (BTK) has a pivotal role in the BCR signaling. Normal B lymphocytes receive signals from BCR that are triggered by binding of the BCR to an external antigen.…”