Direct-acting anticancer (DAA)
peptides are cytolytic
peptides that show promise as novel
anticancer agents. DAA
peptides bind to anionic molecules that are abundant on
cancer cells relative to normal healthy cells, which results in preferential killing of
cancer cells. Due to the mechanism by which DAA
peptides kill
cancer cells, it was thought that resistance would be difficult to achieve. Here, we describe the generation and characterization of two MDA-MB-231
breast cancer cell-line variants with reduced susceptibility to
pleurocidin-family and
mastoparan DAA
peptides.
Peptide resistance correlated with deficiencies in
peptide binding to cell-surface structures, suggesting that resistance was due to altered composition of the cell membrane.
Peptide-resistant MDA-MB-231 cells were phenotypically distinct yet remained susceptible to
chemotherapy. Surprisingly, neither of the
peptide-resistant
breast cancer cell lines was able to establish
tumors in immune-deficient mice. Histological analysis and
RNA sequencing suggested that tumorigenicity was impacted by alternations in angiogenesis and extracellular matrix composition in the
peptide-resistant MDA-MB-231 variants. Collectively, these data further support the therapeutic potential of DAA
peptides as adjunctive treatments for
cancer.