Use of DNA‐alkylating pyrrole‐imidazole polyamides for anti‐cancer drug sensitivity screening in pancreatic ductal adenocarcinoma

BACKGROUND: Activating mutations of the KRAS occurs in >90% of pancreatic ductal adenocarcinoma (PDAC) cases. However, direct pharmacological targeting of the activated KRAS protein has been challenging. We previously reported that KR12, a DNA‐alkylating pyrrole‐imidazole polyamide designed to recognize the KRAS G12D/V mutation, showed an anti‐tumor effect in colorectal cancer. In this study, we evaluated the anti‐tumor effect of KR12 in PDAC. METHODS: KR12 was synthesized by an automated peptide synthesizer PSSM‐8 and tested for anti‐tumor effect in PDAC mouse models. RESULT: KR12 inhibited tumor growth in a spontaneous PDAC mouse model, although the anti‐tumor activity appeared to be limited in a human PDAC xenograft model. We developed a pyrrole‐imidazole polyamide screening process based on the hypothesis that genetic elements otherwise unaffected by KR12 could exert attenuating effects on KRAS‐suppression‐resistant PDAC. We identified RAD51 as a potential therapeutic target in human PDAC cells. A RAD51 inhibitor showed an inhibitory effect on cell growth and affected the cytotoxic activity of KR12 in PDAC cells. CONCLUSION: These data suggested that the simultaneous inhibition of RAD51 and mutant KRAS blockage would be an important therapeutic strategy for PDAC.