SulFex · Sulfite export mechanisms as a therapeutic vulnerability in KEAP1-deficient lung cancer

Non-small cell lung cancer (NSCLC) harboring KEAP1 mutations is associated with a poor prognosis and resistance to conventional therapies. However, KEAP1/NRF2 dysregulation induces metabolic reprogramming, which can be exploited for therapeutic benefit. Our research has uncovered that these cells produce and accumulate high levels of sulfur-containing compounds, a metabolic vulnerability in these cancer cells. To maintain cellular homeostasis and survival, these cells rely on the active export of the toxic metabolite sulfite, presenting a unique therapeutic opportunity.During our ERC Consolidator project, we identified the solute carrier protein SLC26A6 as a transporter of selenite and related anions, including sulfite. We then developed SulfExstatin1, a first-in-class small molecule inhibitor that effectively inhibits human SLC26A6 and blocks sulfite export. By targeting this essential detoxification mechanism, SulfExstatin1 selectively impairs the growth and survival of KEAP1-mutant NSCLC cells while sparing normal cells, thereby minimizing off-target toxicity. Our preliminary studies demonstrate strong efficacy in cell culture, underscoring the potential of this approach as a novel treatment strategy for this aggressive cancer type.Building on these findings, we propose to establish an innovative approach targeting sulfite metabolism in KEAP1-mutant NSCLC and other cancer subtypes with similar metabolic dependencies. This project will involve optimizing SulfExstatin1 and related inhibitors, characterizing their mechanisms of action, and evaluating their efficacy in biochemical assays and in vivo models. Furthermore, we plan to establish a patent framework to protect the intellectual property arising from this project. Ultimately, our goal is to translate this metabolic-targeting strategy into clinical applications, offering new hope for patients with this treatment-resistant lung cancer.