Identifying Cysteine-Dependent Neoantigens Resulting from Missense Substitutions for Cancer Immunotherapy by BiTE Treatment

Abstract:

The KRAS oncogene encodes a GTPase that mediates cell proliferation. The KRAS G12C allele is a missense substitution detected in 19% of human cancer cells (Cekani, 2022). Clinically, KRAS G12C blockers have been recently approved for the treatment of non-small cell lung cancers (NSCLCs) (Nakajima, 2022). G12C drugs like ARS1620 act by covalently bonding to the sulfhydryl group found in cysteine residues. Covalent chelation prevents reactivation of the mutant KRAS G12C peptide. Although effective as a chemotherapeutical, evolution of resistance to KRAS G12C inhibitors has inevitably arisen (Zhang, 2022). Resistance to KRAS G12C inhibitors involves several distinct mechanisms, yet many recalcitrant tumors still possess covalent adduct signatures. Cancer immunotherapy can exploit MHC-I display of ARS1620-haptenated KRAS G12C antigens using bispecific T-cell engager (BiTE) therapy (Zhang, 2022). A BiTE contains two different Fab regions, one specific to CD3(epsilon) and the other binds ARS1620-haptenated antigens presented on MHC-I. BiTEs activate bound T cells to drive apoptosis on nearby haptenated cancer cells (Stieglmaier, 2015). The Cancer Genome Atlas (TCGA) is a growing database of somatic mutations obtained from cancer patient biopsies (Tomczak, 2015). The Catalogue of Somatic Mutations in Cancer (COSMIC) is a curation effort to identify driver mutations of cancer states (Tate, 2019). By blending TCGA with COSMIC, we datamined over 100K point mutations to identify ~4K alleles arrayed across ~500 genes that yield a cysteine residue due to a missense substitution. Our work identifies candidate BiTE targets for a cancer immunotherapy approach involving haptenation by ARS1620.