Anti-tumor peptides for KRAS-mutant lung cancer

KRAS is among the most frequently mutated oncogenes in lung adenocarcinoma, and the recent covalent inhibitors address only a subset of alleles. An alternative to inhibiting the protein is to exploit the fact that the oncogenic state remodels the cell surface, so that mutant cells may be distinguishable from their wild-type counterparts by an extracellular phenotype. Peptide ligands that bind such a phenotype would be useful as targeting moieties for delivery rather than as inhibitors. Identifying them is difficult because the relevant surface determinants are not known in advance, which rules out target-based screening.

The project uses whole-cell phage display biopanning of a 7-residue peptide library against a panel of lung cancer cell lines carrying different KRAS backgrounds, including wild-type and the G12V, G12D and G12C mutants, followed by deep sequencing of the selected populations. Enrichment alone does not separate genotype-associated binding from amplification bias and from binding to features shared by all cell lines, so the counts are analysed with a probabilistic model that assigns each peptide four distinct contributions: unspecific background, counter-selection against pooled wild-type cells, wild-type-associated binding and mutant-associated binding. Candidates are then prioritised by multi-objective optimisation over these components and validated by flow cytometry on the cell panel.

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