STAT3: A Promising Therapeutic Target in Multiple Myeloma

Abstract

Multiple myeloma (MM) is an incurable plasma cell malignancy for which novel treatment options are required. Signal Transducer and Activator of Transcription 3 (STAT3) overexpression in MM appears to be mediated by a variety of factors including interleukin-6 signaling and downregulation of Src homology phosphatase-1 (SHP-1). STAT3 overexpression in MM is associated with an adverse prognosis and may play a role in microenvironment-dependent treatment resistance. In addition to its pro-proliferative role, STAT3 upregulates anti-apoptotic proteins and leads to microRNA dysregulation in MM. Phosphatase of regenerating liver 3 (PRL-3) is an oncogenic phosphatase which is upregulated by STAT3. PRL-3 itself promotes STAT-3 phosphorylation resulting in a positive feedback loop. PRL-3 is overexpressed in a subset of MM patients and may cooperate with STAT3 to promote survival of MM cells. Indirectly targeting STAT3 via JAK (janus associated kinase) inhibition has shown promise in early clinical trials. Specific inhibitors of STAT3 showed in vitro efficacy but have failed in clinical trials while several STAT3 inhibitors derived from herbs have been shown to induce apoptosis of MM cells in vitro. Optimising the pharmacokinetic profiles of novel STAT3 inhibitors and identifying how best to combine these agents with existing anti-myeloma therapy are key questions to be addressed in future clinical trials.

STAT3 Activation and Oncogenesis in Lymphoma

“…Multiple myeloma (MM) is a cancer of plasma cells (terminally differentiated B-cells) in the bone marrow, accounting for 10% of all hematological malignances [104]. Hallmark oncogenic signaling pathways in MM include JAK-STAT3, PI3K/AKT/mTOR, and NF-κB [105,106], in which STAT3 is activated by the IL-6-JAK-STAT3 axis [107,108]. A positive feedback regulatory loop between STAT3 and phosphatase of regenerating liver 3 (PRL-3) is another mechanism underlying STAT3 activation in MM [107].…”

“…Hallmark oncogenic signaling pathways in MM include JAK-STAT3, PI3K/AKT/mTOR, and NF-κB [105,106], in which STAT3 is activated by the IL-6-JAK-STAT3 axis [107,108]. A positive feedback regulatory loop between STAT3 and phosphatase of regenerating liver 3 (PRL-3) is another mechanism underlying STAT3 activation in MM [107]. Hypermethylation and silencing of the negative regulators SOCS1 and SHP1 can also contribute to high STAT3 activity in MM [109,110].…”

“…Hypermethylation and silencing of the negative regulators SOCS1 and SHP1 can also contribute to high STAT3 activity in MM [109,110]. Expression of antiapoptotic pathway genes such as MCL-1, BCL2, and BCL-XL due to STAT3 activation promotes MM cell survival [107,111]. STAT3 activity promotes expansion and activation of myeloid-derived suppressor cells (MDSCs), which mediate immunosuppression and facilitate tumor progression in the MM bone marrow microenvironment [112][113][114].…”

Non‐lethal proteasome inhibition activates pro‐tumorigenic pathways in multiple myeloma cells

“…STAT3 is closely associated with inflammation, tumorigenesis and MM cell survival and it is induced by IL6 which, as we found herein, is over‐secreted following non‐lethal proteasome inhibition in MM cells. STAT3 has been associated with poor survival of MM patients and resistance to lenalidomide, while its inhibition suppressed MM cell growth suggesting that it represents a promising therapeutic target in MM . Consistently, it was found that MM exosomes establish a favourable bone marrow microenvironment which enhanced angiogenesis and immunosuppression through activation of the STAT3 pathway, as well as that STAT3 establishes an immunosuppressive microenvironment during the early stages of breast carcinogenesis to promote tumour growth and metastasis .…”

“…STAT3 has been associated with poor survival of MM patients 36 and resistance to lenalidomide, 37 while its inhibition suppressed MM cell growth 38 suggesting that it represents a promising therapeutic target in MM. 39 Consistently, it was found that MM exosomes establish a favourable bone marrow microenvironment which enhanced angiogenesis and immunosuppression through activation of the STAT3 pathway, 40 as well as that STAT3 establishes an immunosuppressive microenvironment during the early stages of breast carcinogenesis to promote tumour growth and metastasis. 41 Similarly, mounting evidence for STAT6, in both patients and mouse models, supports a model where STAT6 is not a mere bystander, but rather, plays an active role in promoting a transformed phenotype in various types of cancer, 42 including also the establishment of an immunosuppressive tumour microenvironment.…”