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

Authors

Xin Zhou, Gregory H Bird, Mu Yu, Jian-Liang Li, Xzaviar K Solone, Michael C Chung, Juan Guan, Loren D Walensky, Lizi Wu

Published in

Molecular therapy. Oncology. Volume 34. Issue 3. Pages 201331. Sep 17, 2026. Epub Aug 21, 2026.

Abstract

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.

PMID:
42733562
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.

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