Feedback activation of STAT3 and IGF1R/IRS plays a prominent role in mediating drug resistance to a broad spectrum of targeted cancer therapies and chemotherapies. Both the IRS1/2 and STAT3 are major signaling junctions regulated by various oncogenes, and altered during EMT and drug resistance. STAT3 has also been known to play an active role in immune-evasion of tumors and inhibition of STAT3, both in the tumor, as well as in the tumor's microenvironment, may therefore potentiate immune attack on the tumor. NT-219 is a dual inhibitor of STAT3 and IRS1/2 developed by TyrNovo Ltd. to overcome cancer drug resistance. NT-219 inhibits STAT3 phosphorylation and eliminates IRS1/2 in a unique 3-step mechanism: dissociation of IRS1/2 from the IGF1 receptor, induction of IRS1/2 serine phosphorylation, and subsequent degradation by the proteasome. We recently demonstrated that the inhibition of both IRS and STAT3 are required and essential for overcoming drug resistance. NT-219 efficacy was demonstrated in Patient-Derived tumor Xenograft (PDX) models of multiple cancer types: melanoma, sarcoma, pancreatic, colon, lung, and head & neck, when added-on to the approved therapies. In these models, NT-219 overcame acquired resistance to several oncology drug families: inhibitors of EGFR (Tarceva®, Erbitux®, Tagrisso®), MEK (Mekinist®), mutated-BRAF (Zelboraf®), mTOR (Afinitor®) as well as with chemotherapy agents (Gemzar®, 5FU, Oxaliplatin). We recently demonstrated that NT-219 works in synergy also with immune-oncology therapies. By using double autologous PDX models we demonstrated that NT-219 converted non-responding tumors to responders to Keytruda®. It also enhanced the immunotherapeutic potential of Cetuximab. The unique mode of action of NT219 may open a new avenue of combined targeted therapies in a wide range of malignancies, and has the potential to expand response duration and target patient population to the applicable drugs.
Citation Format: Lana Kuperschmidt, Hadas Reuveni, Shani Carmi, Neta Moskovits, Netta R. Shraga, Evgeny Solomonov, Ohad Ronen, Salomon Stemmer, Izhak Haviv. NT219, a novel dual inhibitor of STAT3 and IRS1/2, converts immuno-oncology resistant tumors to responders [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2754.