Abstract 1706: A non-canonical MiT/TFE-dependent NRF2 program is a druggable vulnerability in multiple cancer types

Abstract The transcription factor NRF2 is a master regulator of cellular responses to oxidative stress, contributing to the pathogenesis of autoimmunity, metabolic disorders, and neurodegeneration. Somatic alterations in the NRF2 pathway also contribute to the growth and metastasis of many cancer types including ~30% of lung cancers. Still, the activation of NRF2 has frequently been observed in the absence of known genomic alterations, indicating that other pathways may drive its dysregulation. Further, approaches to target NRF2 pharmacologically have remained elusive. Here, we conducted a screen that identified a small molecule, ML329, exhibiting selective cytotoxicity in cells exhibiting NRF2 dependency and synthetic lethality to NRF2 pathway mutations across 489 cell lines. Surprisingly, we find that melanomas—which rarely have somatic mutations in the NRF2 pathway—were commonly sensitive to ML329. Melanomas were seen to exhibit NRF2-dependent metabolomic and transcriptional programs through the transcriptional activation of the adaptor protein p62/SQSTM1 by the melanocyte master regulator and oncoprotein MITF. This pathway was found to be conserved among all cancers characterized by genomic alterations of the MiT family (MITF, TFEB and TFE3) including subsets of renal cell carcinomas, pediatric sarcomas, and uveal and cutaneous melanomas. Our data identify a previously unrecognized, non-canonical mechanism of NRF2 activation by the MiT family, clarifying the regulation of NRF2 in pathologic and physiologic contexts. Pharmacologic inhibition of NRF2 could be valuable in the treatment of conditions with MITF family dysregulation. Citation Format: Xinbo Luo, Bart Lutterbach, Priya Pancholi, Yeon Sook Choi, Xiao Liu, Phillip Munson, Saqib Faisal, David A. Whipple, Robert A. Smith, Warren S. Weiner, David K. Johnson, Myriam Boukhali, Nicole S. Persky, Matthew G. Rees, Shunsuke Kitajima, David Barbie, Anuradha Roy, Michael Baltezor, Lian Rajewski, William McGuinness, John Haslam, Ananthan Sadagopan, Charles H. Yoon, Cory M. Johannessen, Christine G. Lian, Jason L. Hornick, Srinivas R. Viswanathan, David Liu, Vicki Nienaber, Wilhelm Haas, Frank J. Schoenen, David E. Fisher, Rizwan Haq. A non-canonical MiT/TFE-dependent NRF2 program is a druggable vulnerability in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1706.