Abstract 1132: Exploiting MGMT loss using a new class of DNA modifiers which selectively target tumor DNA and overcome therapy resistance mechanisms across multiple tumor types

Abstract DNA damage response (DDR) defects are common in cancer, and it is well established that these tumor-associated DNA repair vulnerabilities can be exploited for a therapeutic gain. Small molecule inhibitors of DDR proteins have been developed to target these cancers, which are now FDA-approved and/or currently being tested in clinical trials. Our team recently reported on an entirely new approach to exploit DDR defects in cancer, via DNA modification, eliminating the need to target proteins (Lin et al., Science 2022). In this recent study, we demonstrated that our new class of “DNA modifiers (DMs)” can be engineered to exploit loss of O6-methylguanine methyltransferase (MGMT), which leads to robust and selective killing of MGMT-deficient glioma tumors, both in vivo and in vitro. We also found that our approach could overcome acquired and intrinsic defects in another DDR pathway, mismatch repair (MMR), which is a known resistance mechanism to standard-of-care cytotoxic therapies in glioma, including TMZ. Here, we sought to determine the extent to which our approach can be expanded to selectively target a wide range of cancers beyond glioma in which loss of MGMT, as well as acquired and intrinsic MMR defect, are commonly seen at various frequencies. To this end, we profiled over 900 cell line models, as well as several collections of patient-derived cultures derived from several tumor types for sensitivity to our DMs based on MGMT and MMR status in vitro. We then validated our findings in cell line xenograft and patient-derived xenograft models, in vivo. In parallel, we compared the activity of DMs to commonly used, standard-of-care cytotoxic drugs, in vitro and in vivo. Our data indicate that DMs can effectively target MGMT loss, as well as intrinsic and acquired MMR defects, in multiple non-CNS tumor types. Taken together, the findings reported here support an entirely new approach to selectively exploit DDR defects via direct DNA modification. This new approach has the potential to overcome known resistance mechanisms to currently used small molecule inhibitors of DDR proteins, across a broad range of cancers. Citation Format: Bruce Ruggeri, Kyle Tarantino, Ranjini Sundaram, Kingson Lin, Seth Herzon, Joseph Park, Spenser Johnson, Susan Gueble, Ranjit S. Bindra. Exploiting MGMT loss using a new class of DNA modifiers which selectively target tumor DNA and overcome therapy resistance mechanisms across multiple tumor 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 1132.