Direct Targeting Options for STAT3 and STAT5 in Cancer

Abstract

Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

“…Considering that a specific therapy is still missing in LGLL and that current immunosuppressive drugs do not provide satisfying responses, the above-mentioned clinical impact of STAT signaling in LGLL makes these molecules attractive new targets for drug development. Several direct STAT inhibitors interacting with protein domains are available, including Stattic, S3I-201, STA-21 for STAT3 (54) and Pimozide, Stafib2, and Cpd17f for STAT5b (55). However, these compounds induce several off-targets toxicities and severe side-effects that for the time being prevent their use in the clinical setting.…”

Classic and Variants APLs, as Viewed from a Therapy Response

“…Nevertheless, similar to STAT5B [130], dimerization domain of PRKAR1A is dispensable for transformation of murine myeloid progenitors [131]. Clinically, the unique patient shows a good clinical response to ATRA/chemotherapy [76] The signal transducer and activator of transcription (STAT5b) belong to a family of latent cytosolic transcription factors activated by cytokines or growth factors [132]. STAT5 is constitutively activated through multiple mechanisms during hematological transformation.…”

“…The signal transducer and activator of transcription 3 (STAT3) are phosphorylated in response to cytokines and growth factors [132]. Similar to STAT5 fusions, coiled-coil, DNA binding domains and SH3/SH2 domains of STAT3 are fused to RARA.…”

Activation of STAT3 and STAT5 Signaling in Epithelial Ovarian Cancer Progression: Mechanism and Therapeutic Opportunity

“…Moreover, EZH2 can also interact with the STAT5 N-terminal oligomerisation domain, which was shown to be essential for B-cell acute leukemic transformation silencing the kappa light chain expression [48]. Such studies postulate that STAT3/5 interaction with EZH2 could be a valuable target interface for future therapeutic intervention [49], but future studies with EOC model systems are needed.…”