BTK, the new kid on the (oncology) block?

Abstract

In the last decade data piled up indicating that BTK - for twenty years considered as a "private matter" of bone marrow-derived cells - it is expressed and plays important and different roles also outside of the hematopoietic compartment and, most notably, in tumor cells. Initial evidence that BTK plays a critical role in B cell-derived malignancies prompted the chase for specific inhibitors, the forefather of which entered the clinic in a record time and paved the way for an ever increasing number of new molecules to be trialed. The growing interests in BTK also led to the discovery that, in solid tumors, two novel isoforms are mainly expressed and actionable liabilities for target therapy. Remarkably, the different isoforms appear to be involved in different signaling pathways which will have to be attentively specified in order to define the area of therapeutic intervention. In this perspective we briefly summarize the progress made in the last decade in studying BTK and its isoforms in cancer cells and define the open questions to be addressed in order to get the most benefits from its targeting for therapeutic purposes.

Keywords: B-cell leukemia; BTK; BTK-A; BTK-C; p65BTK; solid tumors.

Figure 1

Signaling pathways involving BTK in B cells. BTK is activated downstream of different receptors (BCR, CD19, BAFFR, TLRs, chemokine receptors), being pivotal for relaying activation, proliferation, differentiation, survival, migration and adhesion signals. Different adaptors and kinases convey on BTK activation depending on the stimulated receptor. PI3K-generated PIP3 binding to the N-terminal PH domain allows membrane recruitment and phosphorylation-mediated activation. BTK-mediated phosphorylation activates PLCγ2 leading to IP3 and DAG generation which ultimately trigger NFAT-dependent transcription and RAS-MAPK and NF-kB pathway activation, respectively. In addition, BTK can activate directly the AKT-mTOR pathway.

Figure 2

Transcripts encoding the different BTK isoforms and the corresponding proteins. (A) organization of the BTK-A- and BTK-C/p65BTK-encoding transcripts. The only variation between the two mRNAs is a different exon 1 which is uncoding in BTK-A transcript and encoding in the BTK-C one. In addition, the same mRNA can be translated also from an ATG located in the 4th exon thus giving raise to p65BTK. Gray boxes indicate exons. Translation starts are indicated by colored triangles. (B) Domain organization of the BTK isoforms. Compared to BTK-A BTK-C has an extended PH domain whereas p65BTK miss most of it. Indicated by triangles are the PIP3 binding sites that allow dimerization and membrane translocation. Y551and Y223 are the sites of phosphorylation that regulate BTK activation. C481 is the critical residue (gatekeeper) in the kinase domain targeted by most BTKis.

Figure 3

Overview of the signaling pathways where BTK isoforms are involved in different types of cells. BTK-A activation downstream of a series of receptors expressed in normal, neoplastic and autoreactive B cells (BCR, CD19, BAFFR, TLRs, chemokine receptors), regulates activation, proliferation, differentiation and survival signals. In myeloid cells the same isoform is activated by FcεR and FcγR and TLRs, which is crucial for the activation of the inflammasome. In platelets BTK-A activation is necessary for platelets aggregation triggered by the adhesive receptors. Finally, in some solid tumors, BTK-A pharmacological targeting has revealed its role in promoting the survival of cancer cells. A role for sustaining the survival of breast and prostate cancer cells has been demonstrated for the 80 kDa BTK-C isoform. Targeting p65BTK has proved to overcome the resistance of colon and non-small cell lung cancer cells to chemo- and targeted therapy, besides being a prognostic factor and an actionable target in glioblastoma and ovarian cancer.