Abstract 1125: Analysis of the Genie database for TC-NER deficient cancers sensitive to ITX-0121

Abstract Cells possess a complex DNA damage response (DDR) system, to prevent detrimental mutations from accumulating and being passed on. The genes encoding various DDR components are frequently mutated in cancer cells and provide a potential site for therapeutic intervention. DNA damaging agents, with one exception, are repaired by the global genome repair (GG-NER). The one exception are Illudofulvenes, which hide from the GG-NER and can only be repaired by the transcriptional-coupled repair (TC-NER) pathway. Many cancers are deficient in the TC-NER pathway and cannot properly repair DNA damage. In TC-NER deficient cancer cells the TC-NER polymerase complex becomes blocked by the illudofulvene ITX-0121, disengages from DNA, and the irreversible process of apoptosis. These cancers are 10-fold more sensitive to ITX-0121 than are cancer cells with a functional TC-NER pathway. In contrast, non-replicating or normal cells are minimally affected by and this is reflected in the lack of systemic toxicity in humans administered an illudofulvene. Analysis of the GENIE Database indicates the incidence of TC-NER deficient cancers in solid tumors is ∼13%, and includes all major histological classifications (or ∼175, 000 new patients annually). The highest incidence of TC-NER gene mutations/deletions was for the ERCC2 and ERCC5 genes with an incidence of 2.1% for each. Surprisingly, many patients with an ERCC2 or ERCC5 mutation had a second mutation in another ERCC gene (often ERCC6). The ERCC8 gene has the lowest incidence (0.4%) and the ERCC1 gene had the second lowest incidence of mutations (0.5%), but 65% of ERCC1 mutations were associated with a mutation in another ERCC gene. Based on studies involving double knockouts of TC-NER genes, these cancers have a 20-fold increase in sensitivity to ITX-0121. Histological classifications of cancers with the highest incidence of TC-NER deficiency (>25%) in the GENIE database included bladder, colorectal, endometrial, ovarian, and melanoma. In contrast, bone, renal, and thyroid cancers had a relatively low incidence of <8%. We developed a companion diagnostic to identify TC-NER deficient patients based on this data. Based on prior studies, we believe the MTD of ITX-0121 in humans to be >1.2 mg/kg, but only 0.4 mg/kg will be sufficient for clinical efficacy in TC-NER deficient cancers. Hence, despite administering a cytotoxic agent, one will treat TC-NER deficient cancer patients at a non-toxic dose. Toxicity (if it occurs) should be limited to transient thrombocytopenia based on prior studies. In summary, we are utilizing a Precision Medicine approach to develop a drug for an indication defined by a specific molecular alteration across cancer types, which in this case is the presence of TC-NER deficiency as identified by monoallelic mutations in specific genes coding for proteins in the TC-NER pathway. Citation Format: Michael J. Kelner. Analysis of the Genie database for TC-NER deficient cancers sensitive to ITX-0121 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1125.