Abstract LB460: Aberrant CRTC-CREB activation is required for the development and maintenance of LKB1-inactivated lung cancer

Abstract Non-small cell lung cancer (NSCLC) frequently exhibits genetic alterations that inactivate the tumor suppressor gene STK11 (LKB1), leading to increased tumor growth, metastasis, and resistance to existing therapies, including immune checkpoint blockade. Because it is challenging to directly target an inactive or absent tumor suppressor, exploring downstream pathways affected by LKB1 loss could offer new therapeutic opportunities. LKB1 encodes a serine/threonine kinase that activates AMPK and 12 related kinases, including the salt-inducible kinases (SIKs), which regulate cell growth and metabolism. Genetic evidence strongly supports a critical role for the LKB1-SIK axis in suppressing lung tumor growth. We previously demonstrated that LKB1 loss and subsequent SIK impairment induce the nuclear translocation of CRTC transcriptional co-activators, driving a potent and consistent CRTC/CREB-mediated transcriptional program in lung cancer cells. A dominant-negative CRTC mutant (dnCRTC) that blocks the CRTC-CREB interaction was found to inhibit this oncogenic transcriptional program and suppress the growth of LKB1-inactivated, but not LKB1-wild-type, lung cancer in vitro and in xenograft models. These findings suggest that the CRTC-CREB interaction is critical for the growth and survival of LKB1-inactivated lung cancers; however, its role in tumor initiation, progression, and the immune-suppressive tumor microenvironment remains unclear.In this study, we generated a mouse model harboring a LoxP-STOP-LoxP dnCRTC cassette knocked into the H11 locus (dnCRTC-KI). Combining this model with the established KL (KrasLSL-G12D/+ LKB1fl/fl) lung cancer model produced KL-dnCRTC (KrasLSL-G12D/+ LKB1fl/fl dnCRTC-KI+/) mice. Following intranasal administration of adeno-Cre viruses, dnCRTC-expressing mice (KL-dnCRTC) displayed significantly fewer lung tumor nodules, reduced overall tumor burden, and prolonged survival compared with KL controls (from a median of 12.4 weeks to 22 weeks), indicating that blocking CRTC-CREB interaction suppresses tumor development and improves survival. To further assess the effect of dnCRTC on established tumors, we generated a KL (KrasLSL-G12D/+ LKB1-/-) lung cancer cell line with doxycycline-inducible dnCRTC expression for syngeneic implantation in C57BL/6 mice. Dox-induced dnCRTC reduced CRTC/CREB-mediated target gene expression in cancer cells and decreased tumor burden. The impact of dnCRTC expression on the tumor microenvironment is currently under investigation.Collectively, our findings demonstrate a central role of aberrant CRTC-CREB activation in initiating and driving LKB1-inactive lung cancer. These results highlight the CRTC-CREB interaction as a promising therapeutic target and support further exploration of CRTC-CREB protein-protein inhibitors as novel treatments for this lung cancer subtype. Citation Format: Xin Zhou, Wei Ni, Mu Yu, Xzaviar K. Solone, Yuping Sun, Lizi Wu. Aberrant CRTC-CREB activation is required for the development and maintenance of LKB1-inactivated lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB460.