A novel STAT3 inhibitor W2014-S regresses human non-small cell lung cancer xenografts and sensitizes EGFR-TKI acquired resistance

Abstract

Constitutive activation of signal transducer and activator of transcription 3 (STAT3) is a common feature in human non-small cell lung cancer (NSCLC). STAT3 plays an important role in cancer progression as a driver oncogene and acquired resistance of targeted therapies as an alternatively activated pathway. W2014-S with pharmacophore structure of imidazopyridine, which was firstly reported to be utilized in STAT3 inhibitor discovery, was screened out as a potent STAT3 inhibitor from a library of small molecules. The aim of this study is to investigate the antitumor activities and mechanisms of W2014-S in NSCLC and effect on epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) resistance in vitro and in vivo . Methods: SPR analysis, Co-immunoprecipitation, confocal microscope imaging, and luciferase report gene assays were utilized to determine the mechanisms. Cell viability, colonial survival, wound healing, cell invasion assay, human cancer cell xenografts and PDX tumor xenografts were used to determine antitumor activities. Results: W2014-S disrupted STAT3 dimerization and selectively inhibited aberrant STAT3 signaling in NSCLC cell line. W2014-S strongly suppressed proliferation, survival, migration and invasion of lung cancer cells with aberrant STAT3 activation and inhibited the growth of human NSCLC cell xenografts and PDX tumor xenografts in mouse model. Furthermore, W2014-S significantly sensitized resistant NSCLC cell line to gefitinib and erlotinib in vitro and enhances the anti-tumor effect of gefitinib in TKI-resistant lung cancer xenografts in vivo . Conclusions: Our study has provided a novel STAT3 inhibitor with significant anti-tumor activities in NSCLC and suggests that combination of STAT3 inhibitor such as W2014-S with gefitinib could serve as a promising strategy to overcome EGFR-TKIs acquired resistance in NSCLC patients.

Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer

“…STAT3 is also aberrantly hyperactivated in gastric cancer and promotes the genesis and development of gastric cancer [ 20 ]. Meanwhile, some studies showed that alternatively activated STAT3 plays a prominent role in mediating drug resistance to a broad spectrum of chemotherapies, such as cisplatin [ 21 ] and EGFR-TKIs [ 22 , 23 ]. As a transcription factor, STAT3 is also associated with oxidative response [ 24 ] and may be a potential regulator of ferroptosis.…”

Multicellular Effects of STAT3 in Non-small Cell Lung Cancer: Mechanistic Insights and Therapeutic Opportunities

“…Meanwhile, treatment of tumor-bearing mice with the STAT3 inhibitor LL1 sensitizes resistant A549 NSCLC tumors to gefitinib and leads to a synergistic anti-tumor response [ 264 , 265 ]. These findings were corroborated in a separate study, where treatment of gefitinib- and erolotinib-resistant NSCLC with the STAT3 inhibitor W2014-S sensitized these cells to therapy in vitro and enhanced the anti-tumor efficacy of gefitinib in tyrosine kinase resistant lung cancer xenografts in vivo [ 238 ].…”

“…Small molecule inhibitors that target the SH2 domain of STAT3 (e.g., C188-9, OPB-31121, OPB-51602, W2014-S, BBI-608) have demonstrated potent in vitro and in vivo anti-tumor activity in NSCLC models [ 70 , 236 , 237 , 238 ]. BBI-608 inhibits stemness gene expression, depletes CSCs, and overcomes cisplatin resistance in pre-clinical models of NSCLC [ 70 ], and showed encouraging signs of anti-cancer activity in a phase I/II study of NSCLC patients who received BBI-608 plus weekly paclitaxel (NCT01325441).…”

Ibrutinib reverses IL-6-induced osimertinib resistance through inhibition of Laminin α5/FAK signaling

“…Previously, it was reported that tocilizumab could overcome IL-6-induced resistance to erlotinib, a 1st generation EGFR-TKI 13 . Also, we and others have reported that inhibition of STAT3 could reverse drug resistance to 1st generation EGFR-TKIs 10 , 14 . These data suggest that there is a difference of mechanism between 1st/2nd generation EGFR-TKI and osimertinib.…”