In previous blog, “TPCA-1, a Selective IKK-2 Inhibitor, Alleviates Rheumatoid Arthritis”, we identified TPCA-1 as a selective IKK-2 Inhibitor that alleviates rheumatoid arthritis. Today, I’d like to introduce the anti-tumor activity of TPCA-1. A study from Jing Nan identified that TPCA-1 is a direct dual inhibitor of STAT3 and NF-kB and regresses mutant EGFR-associated human non-small cell lung cancers.

Epidermal growth factor receptor (EGFR) is a clinical effective target to treat a subset of non-small cell lung cancer (NSCLC) with EGFR mutants. However, some EGFR mutations show resistance to tyrosine kinase inhibitors (TKI). The authors found that TPCA-1, a previously reported inhibitor of IkB kinases (IKK), blocked STAT3 recruitment to upstream kinases and attenuated STAT3 activity.

In vitro, TPCA-1 severely blocked STAT3 phosphorylation induced by IL-6 or IFN-α at 500 or 100 nM. By the way, previous study reported that TPCA-1 inhibited JAK2 kinase to suppress STAT3 phosphorylation induced by IL-6. Subsequently, the authors verified the effect of TPCA-1 in HCC827 and H1975 cells (NSCLC cell lines). As a result, TPCA-1 potently suppressed proliferation of HCC827 and H1975 cells but has little effect on A549 cells. The results suggested that TPCA-1 as a STAT3 inhibitor suppresses NSCLC with EGFR mutant selectively.

in addition, in vivo, TPCA-1(10 mg/kg, i.p. daily) inhibited growth of NSCLC with EGFR mutation and potentiates antitumor effect of Gefitinib in xenograft models.

To conclude, TPCA-1 is a promising clinical candidate to treat NSCLC with EGFR mutants. Of course, more in vivo experiments need to be further verified.