APOBEC Mutagenesis in Cancer

University Of Texas Hlth Science Center, San Antonio TX

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Abstract

OVERALL – APOBEC MUTAGENESIS IN CANCER ABSTRACT APOBEC enzymes are single-stranded DNA cytosine-to-uracil (C-to-U) deaminases. APOBEC mutagenesis has emerged as the 2nd largest source and the largest actionable source of mutation in cancer. It impacts 70% of all cancer types and is the dominant mutagen in large numbers of bladder, breast, cervical, head/neck, and lung tumors. APOBEC mutagenesis is defined by signature base substitution mutations (C-to-T and C-to-G mutations) in 5′-TCA and 5′-TCT motifs, but its impact is much broader with many C-to-U deamination events leading to DNA breakage, insertion-deletion mutations, and larger-scale chromosomal aberrations. Importantly, for many cancer types, increased levels of APOBEC associate with detrimental clinical outcomes including drug resistance and metastasis. We therefore hypothesize that APOBEC inhibition will decrease mutation rates, slow tumor evolution, and improve the clinical outcomes of many existing anti-cancer therapies. Three multidisciplinary Projects work together in an integrated and comprehensive manner to test this unifying idea. Project 1 is leveraging structural approaches to delineate atomic interactions between APOBEC enzymes and interacting proteins, nanobodies, nucleic acids (substrates and competitive inhibitors), as well as small molecules. Project 2 is providing chemical innovation to the Program by optimizing nucleic acid-, peptidomimetic-, and small molecule-based APOBEC inhibitors and degraders that will ultimately yield potent, selective, and cell-permeable molecules, with low cytotoxicity. Project 3 is investigating protein-level APOBEC regulatory mechanisms, as well as molecular mechanisms downstream of genomic DNA C-to-U deamination. Cellular and murine systems developed here are also essential for testing candidate APOBEC inhibitors developed and characterized by the combined activities of the Program team [Project 2 (chemistry) with essential support from Project 1 (structural biology), Core B (proteins and assays), Core C (computational optimization), and Core A (administration)]. All Projects are supported by service Cores for administration, proteins and assays, and computational biochemistry and bioinformatics. This is a competitive renewal of a highly productive Program with over 50 publications in the initial support period. The next phase of studies will have both immediate and long-term impacts on multiple cancer types: immediate by producing standardized reagents, novel technologies, and a comprehensive understanding of the molecular mechanism of APOBEC mutagenesis, and long-term through the development of novel chemical matter matter to suppress this mutational process and help improve the efficacy of existing cancer therapies.