Abstract SY26-01: Cancer-resistant tissues: Powerful approach for novel tumor suppressor identification and therapeutic reactivation

Abstract Cancer is a complex group of over 200 different diseases that can develop in a wide variety of tissues and cell types. This has led us to research whether there are any tissues in the human body where cancer develops rarely or never, which would point to the possibility that such tissue types have devised ways of countering cancer formation. Studying them could provide us with novel insights into the prevention or treatment of cancer and information needed for uncovering new tumor suppressor pathways. There are indeed tissues in the human body in which cancer occurs only very scarcely. Whereas the incidence of lung, breast and colorectal cancers is high, we seldom hear of adult skeletal muscle cancer, heart cancer or cartilage cancer, for example. We might argue that cancer rarely develops in these tissues because they are in a post-mitotic state, in a terminally differentiated state, or in some metabolic state that is unfavorable for primary cancer growth or the formation of metastatic niches. However, these tissues are in these states because they express numerous proteins that induce them into these states and others that maintain them in these states. Therefore, identifying such proteins in cancer-resistant tissues and achieving their expression in cancers might impede cancer formation by forcing cancer cells into these unfavorable states (differentiation, cell cycle arrest, metabolic reprogramming, etc.). We looked for novel tumor suppressor proteins and pathways in cancer-resistant tissues, which resulted in a list of 87 candidate genes that might be effective tumor suppressors when expressed in human cancers. In a proof-of-concept study, we found that one of these genes, LACTB (Lactamase B-like), is a highly potent mitochondrial tumor suppressor that acts through the reprogramming of metabolism and cell differentiation in numerous types of cancer, for example breast and ovarian cancer, colorectal cancer, hepatocellular carcinoma, glioma, gastric cancer, melanoma, and lung cancer. Furthermore, we have revealed a unique post-translational strategy cancer cells employ to inactivate LACTB in breast cancer. We have established that one enzymatic substrate of LACTB is LACTB itself, meaning that it possesses a capacity for autoproteolysis, which is important for the modulation of its tumor suppressor activity. Our data show that cancer cells misuse this feature of LACTB to force LACTB into self-degradation. Mechanistically, this is realized through the upregulation of mitochondrial protein MRPS34, which, through interaction with LACTB, is a positive regulator of the autoproteolytic activity of LACTB and a negative regulator of LACTB. Furthermore, we have identified a novel group of chemical compounds that, through their inhibitory effect on LACTB’s autoproteolytic activity, are capable of upregulating LACTB levels in cancer cells, which is demonstrated to significantly inhibit tumor growth in preclinical breast and ovary cell line-derived and patient-derived cancer models. Through the use of in vitro, 3D and in vivo assays, studies utilizing fresh human clinical tumor samples, preclinical analyses and pharmacokinetics, we have uncovered and characterized a novel mechanism by which a mitochondrial tumor suppressor is inactivated in cancer cells and identified, for the first time, a realistic therapeutic intervention for LACTB reactivation. Strategies based on LACTB reactivation might serve as a viable alternative to therapeutic deactivation of oncogenes, which currently dominates the field of cancer therapeutics design. Moreover and importantly, our study of cancer-resistant tissues has laid the foundation for recognizing additional novel tumor suppressors, describing the mechanisms of their action and thus identifying new sensitivities of cancer cells. Citation Format: Zuzana Keckesova. Cancer-resistant tissues: Powerful approach for novel tumor suppressor identification and therapeutic reactivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY26-01.