Abstract B029: Targeting phosphodiesterase: A potential strategy to treat LKB1-mutant cancers

Abstract

Abstract Cancer heterogeneity poses numerous challenges to treatment, underscoring the need for personalized/targeted therapies that align with each patient's specific genetic and molecular disease profile. Metabolic deregulation, often correlating with oncogenic alterations, is commonly observed in cancers. Such deregulation frequently presents metabolic vulnerabilities within the cancer, which could potentially be exploited for targeted therapy. Liver Kinase B1 (LKB1), a protein known for its diverse roles in cellular metabolism and its critical function as a tumor suppressor, ranks as the third most frequently mutated gene in non-small cell lung cancer (NSCLC). LKB1 mutations are linked to accelerated tumor progression and invasion, resulting in adverse clinical outcomes. Our research uncovers a novel role for LKB1 in cyclic nucleotide metabolism, wherein it suppresses a set of phosphodiesterase (PDE) expressions. Specifically, LKB1 represses PDE3 via the activation of the downstream salt-inducible kinase. Our data demonstrate that PDE3 modulators can selectively eliminate LKB1-deficient tumor cells while leaving LKB1-wildtype cells unharmed. However, some LKB1-deficient cells develop resistance due to the loss of SLFN12, whose expression is required for PDE3 modulator-induced cell death. Interestingly, this resistance can be overcome by inducing SLFN12 expression, through either epigenetic inhibitors or cAMP inducers. These findings not only broaden our understanding of the role of LKB1 in metabolic regulation but also suggest a promising strategy for targeted therapy against LKB1-mutant cancers. Citation Format: Catherine Rono, Xiaohu (Mark) Tang. Targeting phosphodiesterase: A potential strategy to treat LKB1-mutant cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B029.