The Role Of IL-6/STAT3 Signaling Pathway In Cancer Drug-resistance And Its Small Molecule Inhibitors Study

Cancer drug resistance remains a major problem facing chemotherapy or targeted therapy.Cancer cells adapt multiple regulatory mechanisms to deal with perturbations in cellular homeostasis,including feedback loops and cross-talk between the major signaling pathways.While some of these mechanisms are critically required to help cells survive under dynamic physiological circumstances,they also pose a major impediment to cancer treatments.Studying interactions between receptor tyrosine kinase(RTK)-dependent signaling pathways can help to design rational and more effective combination therapies for cancer.Signal Transducer and Activator of Transcription 3(STAT3)plays crucial roles in several cellular processes such as cell proliferation and survival,and has been found to be aberrantly activated in many cancers.Much research has explored the leading mechanisms for regulating the STAT3 pathway and its role in promoting tumorigenesis.We focus here on recent evidence suggesting that feedback activation of STAT3 plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies.This research highlights the potential of co-targeting STAT3 and its primary target to overcome drug resistance,and investigated repurposing clinically approved drugs as STAT3 pathway inhibitors,in combination with the FDA approved RTK inhibitors(TKIs),to improve clinical outcome of cancer treatment.Currently,there is no effective chemotherapy for pancreatic carcinoma(PC)and colorectal cancer(CC).As a result,pancreatic carcinoma(PC)and colorectal cancer(CC)have a poor clinical outcome and prognosis.Treatment of these two types of cancers has become a hotspot in cancer research.MEK inhibitors have been tested for PC and CC treatment in clinical trials and preclinical studies.However,the mechanisms mediating intrinsic resistance to MEK inhibition are not fully characterized.Here,we identified that STAT3 was significantly activated following the MEK inhibition using AZD6244,PD98059 and Trametinib in K-Ras mutant pancreatic and colon cancer cells.The STAT3 activation may be important for the MEK inhibitor resistance in these K-Ras mutant cancer cells.Results of this research show that dual inhibition of STAT3 and MEK using the STAT3 inhibitor LY5 and MEK inhibitor Trametinib exerted significant anti-tumor cell efficacy in K-Ras mutant pancreatic and colon cancer cells in vitro.In addition,Trametinib showed increased suppression on tumor growth in vivo in STAT3 knockdown pancreatic cancer cells compared with tumor growth of control cells without STAT3 knockdown.Taken together,our results suggest the induced STAT3 activation as a possible mechanism for the resistance to MEK inhibitor and demonstrate the potentials of a combination therapy using MEK and STAT3 inhibitors in pancreatic and colon cancers harboring K-Ras mutant proteins.PC is one of the most lethal forms of cancer,and most patients survive less than a year after diagnosis.Moreover,pancreatic cancer is intrinsically resistant to cytotoxic therapies targeting Epidermal Growth Factor Receptor(EGFR).The poor clinical outcome highlights an urgent need for probing the underlying drug resistance mechanism and developing new therapies.We performed a pilot study and identified a novel mechanism of resistance to EGFR inhibition,by which STAT3 is activated via a feedback activation of EGFR inhibition.Interestingly,EGFR itself is involved in oncogenesis of pancreatic cancer.In preliminary experiments we identified an additional cross-talk between EGFR and STATS.Specifically,we found that the inhibition of EGFR with inhibitors erlotinib and afatinib induced STAT3 phosphorylation in pancreatic cancer cells.Based on this body of evidence,this study hypothesized that the reciprocal cross-talk between the EGFR and STAT3 pathways leads to resistance to both STAT3 and EGFR inhibitors.We further hypothesized that combined inhibition of both STAT3 and EGFR pathways would result in a synergistic suppression of pancreatic tumor cell growth in vitro and in vivo as compared with the inhibition of either STAT3 or EGFR single pathway.In support of these hypotheses,our results demonstrated that knockdown of either EGFR or STAT3 could sensitize pancreatic cancer cells to LY5 or erlotinib.respectively.In addition,simultaneous inhibition of EGFR and STAT3 using the erlotinib and LY5 showed synergistic suppressive effects in multiple pancreatic cancer cell lines.Furthermore,we observed stronger suppression of pancreatic tumor growth in mice when both STAT3 and EGFR were inhibited.These preliminary results strongly support that simultaneous inhibition of STAT3 and EGFR is a more effective therapeutic strategy for pancreatic cancer.Currently,few STAT3 inhibitors are available for cancer therapy.We have developed three novel oral bioavailable STAT3-selective inhibitors L44H37,L49H37 and L49H8 for potential PC therapy.An alternative way of cancer drug discovery is to develop therapeutic agents from natural products that are effective,safe,and affordable.Rhein is a lipophilic anthraquinone abundantly available in medicinal herbs in China.Emerging evidence suggests that rhein has significant anti-tumor effects,supporting the potential uses of rhein as an anti-tumor agent.However,rhein has not yet been tested in pancreatic cancer,and the exact target of rhein remains unclear.Using multiple ligand simultaneous docking(MLSD)screening,we identified rhein as a potential inhibitor of STAT3.Bioassay results show that rhein reversed resistance of EGFR-TKIs in pancreatic cancer in vitro.Furthermore,rhein alone may act as a single-agent for PC therapy by blocking the(interleukin-6)IL-6/STAT3 pathway,or it can be combined with other anticancer drugs to reduce drug resistance caused by IL-6/STAT3 signaling reactivation.We also identified alantolactone as a direct STAT3 inhibitor with potent activity against PC.Using a mechanism-based screening,we also identified the clinically-relevant antidiarrheal drug niclosamide as a potent inhibitor of STAT3 that shows antitumor activity against PC and CC.So far there have been limited data in clinical trials on the therapeutic efficacy of any given STAT3 inhibitor,in light of synergism with either standard treatments or experimental treatments such as EGFR or MEK inhibitors.For other drugs used in clinical trials,their physicochemical properties,pharmacokinetics,and safety should be guaranteed.We expect that repositioning of existing drugs for new indications could save costs and time in drug development.Parallel inhibition of RTK and STAT3 pathways using approved kinase agents and FDA drugs as off-target STAT3 inhibitors deserves further preclinical investigation.