(ChemotherapyAdvisor) – A large, multinational group of researchers, including those at M.D. Anderson Cancer Center, Houston, TX, published a study identifying a novel rationale for combination therapy against esophageal adenocarcinoma (EAC).
Mechanisms of oncogenesis for EAC — the most prevalent esophageal cancer type in the United States — were the subject of the study, which was entitled “The Crosstalk of mTOR/S6K1 and Hedgehog Pathways” and published in the March 20 issue of Cancer Cell. The TNF-α/mTOR pathway and aberrant activation of Gli1, a downstream effector of the Hedgehog (HH) pathway, are known oncogenic mechanisms that mediate the development of EAC.
The FDA has approved the mTOR inhibitor RAD-001 (Afinitor) and the Hedgehog inhibitor GDC-0449 (Erivedge) for use in other types of cancer. In this study, the combination of these two drugs significantly reduced the tumor burden by 90% in a mouse model of EAC, while the mTOR inhibitor RAD-001 alone had virtually no effect.
“In this study, we found that an activated mTOR/S6K1 pathway promotes Gli1 transcriptional activity and oncogenic function through S6K1-mediated Gli1 phosphorylation at Ser84, which releases Gli1 from its endogenous inhibitor, SuFu,” the authors wrote. “Moreover, elimination of S6K1 activation by an mTOR pathway inhibitor enhances the killing effects of the HH pathway inhibitor. Together, our results established a crosstalk between the mTOR/S6K1 and HH pathways, which provides a mechanism for SMO-independent Gli1 activation and also a rationale for combination therapy for EAC.”