azd-1480 and Breast-Neoplasms

The aberrant activation of STAT3 occurs in many human cancers and promotes tumor progression. Phosphorylation of a tyrosine at amino acid Y705 is essential for the function of STAT3. Synthesized carbazole derived with fluorophore compound 12 was discovered to target STAT3 phosphorylation. Compound 12 was found to inhibit STAT3-mediated transcription as well as to reduce IL-6 induced STAT3 phosphorylation in cancer cell lines expressing both elevated and low levels of phospho-STAT3 (Y705). Compound 12 potently induced apoptosis in a broad number of TNBC cancer cell lines in vitro and was effective at inhibiting the in vivo growth of human TNBC xenograft tumors (SUM149) without any observed toxicity. Compound 12 also effectively inhibited the growth of human lung tumor xenografts (A549) harboring aberrantly active STAT3. In vitro and in vivo studies showed that the inhibitory effects of 12 on phospho-STAT3 were through up-regulation of the protein-tyrosine phosphatase PTPN6. Our present studies strongly support the continued preclinical evaluation of compound 12 as a potential chemotherapeutic agent for TNBC and cancers with constitutive STAT3 signaling.

Topics: Animals; Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Screening Assays, Antitumor; Enzyme Induction; Female; Heterografts; Humans; Interleukin-6; Lung Neoplasms; Mice, Inbred BALB C; Mice, Nude; Naphthalenesulfonates; Neoplasm Transplantation; Phosphorylation; Protein Tyrosine Phosphatase, Non-Receptor Type 6; STAT3 Transcription Factor; Structure-Activity Relationship; Transcription, Genetic

We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Transformation, Neoplastic; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Interleukin-6; Janus Kinase 3; Mice; Mice, Knockout; Neoplasm Metastasis; Neoplasms; Pyrazoles; Pyrimidines; Signal Transduction; STAT3 Transcription Factor; Tumor Microenvironment