Targeting LKB1-inactivated lung cancers with a stapled peptide inhibitor of the CRTC-CREB pathway

Non-small cell lung cancers (NSCLCs) with inactivation of the tumor suppressor LKB1 are common and respond poorly to current therapies. We previously identified aberrant activation of the CRTC-CREB transcriptional pathway as a key driver of malignancy in LKB1-deficient lung cancer. In this study, we developed stabilized α-helical peptides, termed stabilized alpha helices of the CREB binding domain (SAH-CBDs), which were designed to disrupt the CRTC-CREB protein-protein interaction. SAH-CBD peptides adopt a stable, bioactive α-helical conformation, bind directly to CREB, and effectively block CRTC-CREB complex formation in vitro. Importantly, SAH-CBDs penetrate cells without causing membrane disruption, inhibit CREB-dependent transcription, and selectively suppress the growth of LKB1-null lung cancer cells, with minimal effects on LKB1-wild-type cells. These findings establish SAH-CBDs as a mechanistic tool and a prototype therapeutic for targeting a key transcriptional vulnerability in LKB1-inactivated NSCLC.