P62.07 Investigation of Metabolic Vulnerabilities Specific to STK11-mutant Lung Cancer

Abstract

Tumor suppressor Serine/Threonine Kinase 11 (STK11) is inactivated in 25-30% of patients with lung adenocarcinoma. Functionally, it is the predominant upstream kinase of adenosine monophosphate-activated protein kinase (AMPK), a key regulator in cell metabolism maintaining energy homeostasis. However, no clinical targeted therapies are available for STK11-mutant lung cancer. An altered metabolism is a characteristic of cancer and differs in cancer types, histological subtypes or genetic backgrounds. Therefore, identifying metabolic vulnerabilities specific to a certain cancer subtype/genetic mutation is essential in terms of precision oncology. Mitochondrial Solute Carriers (SLC) transport various metabolites through the inner membrane of the mitochondria, thereby supporting rapid growth of cancer cells, which plays a critical role in tumor initiation and progression. In lung cancer, it remains to be defined whether the STK11 mutation confers a specific metabolic vulnerability. Candidate genes (N = 53) in the SLC family were then investigated. We integrated the transcriptomic and whole-exome sequencing data from the TCGA (The Cancer Genome Atlas) lung adenocarcinoma cohort (N = 507). Genetically mutually exclusive and co-occurring analysis was performed with open-source bioinformatic tools R (https://www.r-project.org). Integrated analyses reveal that, in the SLC family, SLC25A10 is the most strikingly overexpressed gene in clinical samples of patients with lung adenocarcinoma compared to the matched normal lung tissue. More importantly, compared to the corresponding wild-type lung adenocarcinoma tumor samples, upregulated SLC25A10 is exclusively associated with STK11 mutations while not with other frequently-altered genes (> 5% in lung cancer; TP53, RB1, NF1, EGFR, KRAS, MET, ALK). This exclusivity suggests that SLC25A10 is a potential target in lung cancer harbouring STK11 mutations. Further, analysis of the genetic changes (gene mutations or copy number) of SLC25A10 and STK11 with regard to their exclusion and co-occurrence status revealed a significant, mutually exclusive pattern (adjust p-value < 0.0001), indicating functional redundancy between the two genes in the pathogenesis of lung adenocarcinoma. In the present in silico analysis, we identified that SLC25A10 might play a critical role in tumor progression of lung cancer with STK11 mutations. Therefore, we concluded that the altered metabolic pathways in lung cancer harbouring STK11 mutations might be a potential therapeutic target in this cancer type.