The presence of abnormal nucleoli has been used as a marker for aggressive cancers for over 100 years. The nucleolus is the location for ribosomal RNA (rRNA) biogenesis, which requires approximately 80% of the energy generated by cancer cells. The first step of rRNA biogenesis is the transcription of pre-rRNA, which involves the binding of TIF-IA/RNA Pol I to the UBF/SL1 complex at the rDNA promoter. Many oncogenic mutations, such as Myc amplification and AKT activation, have been associated with the promotion of pre- rRNA synthesis. However, as pre-rRNA synthesis is a housekeeping function, direct targeting of pre-rRNA synthesis for cancer therapy has been controversial. Lung cancer is the leading cause of cancer death in the United States, with the majority of patients having non- small cell lung cancer (NSCLC). The 3rd most commonly mutated gene in NSCLC adenocarcinoma is the serine/threonine kinase LKB1 (STK11), and ~25,000 patients have mutations in LKB1. We recently discovered that LKB1 protein promotes TIF-IA-mediated pre-rRNA synthesis when intracellular UTP is down-regulated, and LKB1-mutant cells lacking such regulation are prone to apoptosis. Based upon these preliminary and published data, we hypothesize that LKB1 inactivation in NSCLC represents a unique acquired tumor vulnerability that can be targeted because cells deficient in LKB1 have lost the ability to promote TIF-IA mediated transcription. The objectives of this proposal are i) to define the molecular mechanism underlying the regulation of TIF-IA mediated pre-rRNA transcription by LKB1, and ii) to determine whether pharmacologic inhibition of de novo uridine monophosphate (UMP) synthesis can specifically suppress LKB1-mutant lung tumors in vivo. These objectives will be met by performing preclinical mouse trials in a unique and clinically- relevant genetically-engineered mouse model (GEMM) and patient derived xenograft (PDX) models to examine inhibition of de novo UMP synthesis by leflunomide as a strategy for inhibiting LKB1-mutant tumors. Since leflunomide is a commonly used clinical agent, we propose that the data from this study will provide a rational foundation to develop a future clinical trial with this inhibitor specifically targeting patients with LKB1 loss-of-function mutations.
Cancer cells with a defective LKB1 signaling pathway are vulnerable to cell death induced by the depletion of intracellular UTP because LKB1 maintains TIF-IA-mediated pre-rRNA synthesis under such conditions to promote cell survival. Hence, therapeutic approaches aiming at the specific elimination of cancer cells with defects in the LKB1 signaling pathway should induce fewer side effects in normal cells and will also not be susceptible to genetic instability-based drug resistance. The completion of this proposed study should result in the development of a novel therapeutic approach for the treatment of lung cancers with LKB1 inactivation.
| Liu, Fakeng; Liu, Yuan; Liu, Xiuju et al. (2018) Inhibition of IGF1R enhances 2-deoxyglucose in the treatment of non-small cell lung cancer. Lung Cancer 123:36-43 |
| Zhang, Jun; Nannapaneni, Sreenivas; Wang, Dongsheng et al. (2017) Phenformin enhances the therapeutic effect of selumetinib in KRAS-mutant non-small cell lung cancer irrespective of LKB1 status. Oncotarget 8:59008-59022 |
