Abstract 2775: CPS1 as a therapeutic target and prognostic indicator in LKB1-inactivated lung adenocarcinoma
Authors: Celiktas Muge , Tanaka Ichidai , Tripathi Satyendra Chandra , Fahrmann Johannes F. , Aguilar-Bonavides Clemente , Villalobos Pamela , Delgado Oliver , Dhillon Dilsher , Dennison Jennifer B. , Ostrin Edwin J. , Wang Hong , Behrens Carmen , Do Kim-Anh , Gazdar Adi F. , Hanash Samir M. , Taguchi Ayumu 
Published: July 2017

Abstract
Liver Kinase B1 (LKB1), encoded by STK11, is a tumor suppressor and somatically mutated in approximately 20% of lung adenocarcinoma. Aside from the effects of LKB1 inactivation on tumor initiation, LKB1-mutant cancers are biologically distinct from cancer with functional LKB1, and the loss of LKB1 uniquely confers invasive and metastatic properties in genetically engineered mouse models of cancer. While various pathways, including energy metabolism, cell polarity, and cell growth, are regulated by LKB1 and can play a pleiotropic role in cancer initiation and progression, no therapies are currently available for clinical use that specifically target LKB1 inactivation. Therefore, elucidation of the functional mechanisms associated with LKB1 inactivation has translational relevance.
We analyzed proteomic profiles of 45 lung adenocarcinoma cell lines with and without LKB1 inactivation to identify molecular features associated with LKB1 inactivation. Carbamoyl phosphate synthase 1 (CPS1) was identified as a markedly overexpressed protein in LKB1-inactivated lung adenocarcinoma cell lines. CPS1 is the first rate-limiting mitochondrial enzyme in the urea cycle, and plays an intricate role in arginine and pyrimidine metabolism. CPS1 knockdown reduced cell growth, decreased levels of metabolites associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with conventional chemotherapy agents including gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis using 305 lung adenocarcinoma tumors revealed that CPS1 was expressed in 65.7% of LKB1-negative and only 5.0% of LKB1-positive lung adenocarcinomas. In addition, CPS1 expression was significantly and independently associated with poor overall survival of lung adenocarcinoma patients (P &lt; 0.0001, HR = 3.03, 95% CI 1.74-5.25). Concordant with the results of tissue microarray, analysis of the Cancer Genome Atlas (TCGA) dataset consisting 403 lung adenocarcinomas revealed that high CPS1 mRNA expression was significantly associated with worse overall survival and is an independent prognostic indicator of lung adenocarcinoma (P = 0.005, HR = 2.31, 95% CI 1.28-4.16). Our findings suggest functional relevance of CPS1 and its association with worse outcome in LKB1-inactivated lung adenocarcinoma. Therefore, CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling us to personalize the treatment of LKB1-inactivated lung adenocarcinoma.
Citation Format: Muge Celiktas, Ichidai Tanaka, Satyendra Chandra Tripathi, Johannes F. Fahrmann, Clemente Aguilar-Bonavides, Pamela Villalobos, Oliver Delgado, Dilsher Dhillon, Jennifer B. Dennison, Edwin J. Ostrin, Hong Wang, Carmen Behrens, Kim-Anh Do, Adi F. Gazdar, Samir M. Hanash, Ayumu Taguchi. CPS1 as a therapeutic target and prognostic indicator in LKB1-inactivated lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2775. doi:10.1158/1538-7445.AM2017-2775