Abstract C043: Targeting TXNRD1 with a competitive inhibitor exposes an Achilles heel of SCLC

Abstract

Abstract Targeting TXNRD1 to kill cancer cells has long been discussed as a promising strategy for the following reasons: 1) TXNRD1 over-expression was repeatedly identified as having a statistically significant association with poor prognosis. 2) It is suggested to be a key player in redox regulation, with a lower dependency in most normal adult cells and tissues than in cancer cells. Last but not least, potent inhibitors of TXNRD1 activity cause cytotoxicity in cancer cells. Despite this highly plausible and promising target profile, the success rate of TXNRD1 inhibitors has been disappointing in preclinical and clinical studies. One reason for this lack of success might be the physicochemical shortcomings of lead compounds, which pose liabilities in the area of bioavailability, stability, and dose limiting side effects. Auranofin, so far the most studied inhibitor of TXNRD1, is a prominent example for these kind of problems, but there are also more recent reports which show that it is demanding to improve the balance between cytotoxicity and selectivity in order to achieve more efficacious and durable tumor suppression. In addition, it is possible that TXNRD1 is not a critical target for all cancer entities, but rather plays critical roles only in a limited set of cancer entities or subtypes thereof. We have identified a class of dinuclear dithiocarbamate gold complexes, with superior efficacy and selectivity for TrxR1, which bind in competition with the TrxR1 substrate thioredoxin-1 (Trx1). Consequently, cells which express higher levels of Trx1, like most cancer and normal cells, are resistant while cells expressing low levels of Trx1, like SCLC, are hypersensitive to the drug. Our data show that all tested SCLC-derived cell lines and primary isolates are hypersensitive to the drug, independent of their resistance status to cisplatin. Unlike most other gold complexes, our drug is devoid of activity on the glutathione system and the proteasome at concentrations cytotoxic to cells. Most importantly, we observe oxidative stress only in the cytoplasm, but not in mitochondria, contributing to a low general toxicity profile. Finally, in SCLC animal models, the inhibitor eradicates residual tumor cells surviving first line therapy and completely prevents tumor recurrence. The safety profile in mouse is favorable for long term treatment and is compatible with first line therapy (cisplatin/etoposide). We present data describing the discovery of the lead compound and its optimization towards improved formulation and on-target activity as well as enhanced cytotoxicity on large 3-D aggregates of tumor cells. We also present a biomarker concept which explains the susceptibility of SCLC but also shows a rational to extend the use of our drug for other cancer (sub-) entities. Citation Format: Nikolas Peter Gunkel, Eberhard Amtmann, Pjotr Fabrowski, Sanaz Taromi, Tobias Dick. Targeting TXNRD1 with a competitive inhibitor exposes an Achilles heel of SCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C043. doi:10.1158/1535-7163.TARG-19-C043