SC-2001 Overcomes STAT3-mediated Sorafenib Resistance through RFX-1/SHP-1 Activation in Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma is the fifth most common solid cancer worldwide. Sorafenib, a small multikinase inhibitor, is the only approved therapy for advanced HCC. The clinical benefit of sorafenib is offset by the acquisition of sorafenib resistance. Understanding of the molecular mechanism of STAT3 overexpression in sorafenib resistance is critical if the clinical benefits of this drug are to be improved. In this study, we explored our hypothesis that loss of RFX-1/SHP-1 and further increase of p-STAT3 as a result of sorafenib treatment induces sorafenib resistance as a cytoprotective response effect, thereby, limiting sorafenib sensitivity and efficiency. We found that knockdown of RFX-1 protected HCC cells against sorafenib-induced cell apoptosis and SHP-1 activity was required for the process. SC-2001, a molecule with similar structure to obatoclax, synergistically suppressed tumor growth when used in combination with sorafenib in vitro and overcame sorafenib resistance through up-regulating RFX-1 and SHP-1 resulting in tumor suppression and mediation of dephosphorylation of STAT3. In addition, sustained sorafenib treatment in HCC led to increased p-STAT3 which was a key mediator of sorafenib sensitivity. The combination of SC-2001 and sorafenib strongly inhibited tumor growth in both wild-type and sorafenib-resistant HCC cell bearing xenograft models. These results demonstrate that inactivation of RFX/SHP-1 induced by sustained sorafenib treatment confers sorafenib resistance to HCC through p-STAT3 up-regulation. These effects can be overcome by SC-2001 through RFX-1/SHP-1 dependent p-STAT3 suppression. In conclusion, the use of SC-2001 in combination with sorafenib may constitute a new strategy for HCC therapy.

Sorafenib with ASC-J9®synergistically suppresses the HCC progressionviaaltering the pSTAT3-CCL2/Bcl2 signals

“…Early mechanism dissection suggested that Sorafenib might function through inhibiting Raf‐1 and B‐Raf and the receptor tyrosine kinase activity of VEGFRs 1, 2 and 3 and PDGFR‐β . However, recent reports indicated that STAT3 activation also played a key role in the development of Sorafenib resistance in HCC cell lines . Our clinical studies using human HCC samples also demonstrated that higher expression of activated p‐STAT3 might indicate worse recurrence free survival under Sorafenib treatment.…”

“…To dissect the potential molecular mechanism(s) how ASC‐J9 ® combined with Sorafenib suppressed HCC cell invasion and proliferation, we first focused on p‐STAT3 signals as early studies indicated that Sorafenib resistance in HCC might be linked to altered p‐STAT3 signals . Interestingly, Lin et al .…”

The STAT3 pathway as a therapeutic target in head and neck cancer: Barriers and innovations

“…The novel small molecule SC-2001 was shown to inhibit the transcriptional activities of STAT3 by enhancing SH-1 activity in hepatocellular carcinoma (HCC) cells [108]. This molecule has also been studied in combination with sorafenib, a multikinase inhibitor approved for treatment of unresectable HCC, advanced RCC, and thyroid cancer, where it was shown to overcome sorafenib resistance through the SH-1 pathway in HCC cell lines [109]. …”

Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer

“…Several drug-treated 'oncogeneaddicted' cancer cells induce a positive feedback loop leading to STAT3 activation, consequently promoting cell survival and limiting overall drug response. For example, overactivation of STAT3 is associated with resistance to chemotherapy (i.e., taxol [137]) and targeted agents used in a variety of tumors, including the anti-EGFR mAb cetuximab, the anti-HER2/neu receptor mAb trastuzumab and TKIs erlotinib, sunitinib, sorafenib, crizotinib and imatinib mesylate [138][139][140][141]. The combined use of these agents with STAT3 inhibitors should be investigated in clinical trials, even to understand if STAT3 inhibitors should be administered from the start of targeted therapy to reduce primary resistance or at time of acquired resistance.…”