Pharmacological Inhibition of Oncogenic STAT3 and STAT5 Signaling in Hematopoietic Cancers

Abstract

Signal Transducer and Activator of Transcription (STAT) 3 and 5 are important effectors of cellular transformation, and aberrant STAT3 and STAT5 signaling have been demonstrated in hematopoietic cancers. STAT3 and STAT5 are common targets for different tyrosine kinase oncogenes (TKOs). In addition, STAT3 and STAT5 proteins were shown to contain activating mutations in some rare but aggressive leukemias/lymphomas. Both proteins also contribute to drug resistance in hematopoietic malignancies and are now well recognized as major targets in cancer treatment. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations during the last decade. This review summarizes the current knowledge of oncogenic STAT3 and STAT5 functions in hematopoietic cancers as well as advances in preclinical and clinical development of pharmacological inhibitors.

STAT3 and p53: Dual Target for Cancer Therapy

“…The SH2 domain is necessary for STAT3 dimer formation and phosphorylation which are recruited to tyrosine-phosphorylated receptor complexes; thus, targeting the SH2 domain is a prospective approach. Some SH2 domain inhibitors have been used in preclinical research (S3I-201 and derivatives) or entered clinical trials (OPB-31121, OPB-51602) for hematologic cancer treatment [ 77 ]. However, STAT3 interacts with NF-κB subunits in the absence of Tyr705 phosphorylation or is modified at other sites such as Ser727 to activate transcription [ 49 , 78 ].…”

Targeting STAT3 and STAT5 in Cancer

“…The chapter is prefaced by a review outlining a brief history and identification of the involvement of STAT3 and STAT5 gene products and their current mutational landscape. The major gain-of-function driver mutations in hematologic cancers are highlighted, as well as detailed reports of indirect and direct inhibitors of STAT3 and STAT5 and their current stage of clinical development [19]. These themes are further developed by Orlova et al, where the current paradigms in direct small molecule targeting of STAT3 and STAT5 are explored in the context of unphosphorylated STATs, as well as chromatin remodeling [20].…”

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…Combination with TKIs showed dramatic increase in effects, whereas monotherapy of either was evidently inferior [ 142 ]. However, STAT3/5 inhibition may be less effective than JAK inhibition as other STATs may compensate for STAT3/5 loss [ 143 ].…”