IL-6 Secretion & ALK Suppression in Advanced Prostate Cancer

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Prostate cancer cells with a specific mutation profile have been found to secrete IL-6, which in turn activates the oncogene MYC to drive cell proliferation and disease progression, according to a study published in Cancer Discovery.¹

Based on the study results, "It suggested immediately that cell-cell communication is very, very important to make the cells resistant to therapy and very aggressive," said Lloyd Trotman, PhD, an associate professor at Cold Spring Harbor Laboratory, New York, and research team leader.²

The involvement of IL-6 in disease progression may have implications for treatment. There is immense variability in patient responses to hormone therapy, and currently it is unclear which individuals will respond.

"For one man this therapy might be great, might reduce disease burden dramatically for many, many, years, and be an extreme benefit. For others there's almost no response, and it's still not clear to clinicians who is who," said Trotman.²

The findings come from research using a prostate cancer mouse model developed by the investigators called RapidCaP. They previously demonstrated that the simultaneous loss of Pten and Trp53 genes triggers a highly penetrant metastatic cancer. Examination of the secretion profiles of the double-deletion cancerous cells revealed an abundance of IL-6 among the 40 profiled cytokines. Furthermore, IL-6 was shown to be upregulated in these cells.

The data showed that autocrine/paracrine IL-6 signalling induced STAT3 phosphorylation and subsequent increased expression of its transcriptional target, MYC, a functionally validated driver of prostate cancer. Thus, the expression of MYC in response to IL-6/STAT3 signaling directly results from the Pten/Trp53 codeletion and drives cell proliferation. 

Data also indicated that activation of MYC by secreted IL-6 is accompanied by PHLPP2-mediated suppression of AKT. Together, this drives proliferation and castration resistance.

These findings present drug targeting opportunities. Elevated IL-6 has been observed during the advanced stages of many cancers, including multiple myeloma, non-small cell lung carcinoma, and prostate, colorectal, renal, breast, and ovarian cancers. Therapeutic antibodies that target IL-6 (siltuximab) or JAK/STAT3 signalling (ruxolitinib) have shown mixed results in metastatic castration-resistant prostate cancer.

“We hope that future trials on IL-6/STAT3 pathway inhibition may benefit from our modeling results by pointing to MYC for patient selection and monitoring of drug efficacy,” wrote lead author Dawid Nowak, PhD, and colleagues.

References:

• Nowak DG, Cho H, Herzka T, et al. (2015). MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2. Cancer Discovery.
• News Medical. (2015). Researchers identify immune system marker that drives therapy-resistant prostate cancer.