Abstract 2845: A Rb phosphorylation code associated with lung cancer metastasis

Abstract

Lung cancer is characterized by its poor prognosis, aggressiveness, and proclivity for early metastasis. Non-small cell lung cancer (NSCLC) it’s the most common type of lung cancer with a five-year survival rate of 18%. Most predictors of metastasis and recurrence of NSCLC rely on post-resection evaluation of tumor histology, which is a severe limitation since only 15% of the patients are diagnosed with resectable disease. Hence, there is a need to characterize biomarkers with metastasis-predicting value in pre-resection small biopsy specimens. In addition to the proclivity for metastasis, another feature of lung cancers is the inactivation of the retinoblastoma protein (Rb). The retinoblastoma protein (Rb) is a tumor suppressor inactivated due to hyper-phosphorylation in most human cancers, including NSCLC. Our preliminary data relates the Rb S249/T821 phosphorylation signature to an epithelial-to-mesenchymal transition (EMT), a trait strongly associated to metastasis. We found that cells that have hyperphosphorylated Rb in residues S249/T821 express EMT markers such as decreased expression of E-cadherin and integrin α5 as well as increased expression of N-cadherin, Vimentin, and p-FAK. We propose to focus on the cell adhesion and migration-related kinase Cdk5 with its activator p39 as the kinase responsible for engendering the Rb S249/T821 phosphorylation signature. Our hypothesis is that Rb phosphorylation in S249 and T821 due to CDK5 activity can have prognostic value by being associated with a metastatic phenotype and EMT. Studies performed in a tissue microarray in a population of NSCLC adenocarcinoma that had undergone EMT found an up-regulation in p39 and that its expression is correlated with metastasis. Knockdown of CDK5 induced a decrease in phosphorylation of Rb S249/T821 with a decrease in E-cadherin expression. These data suggest that CDK5-dependent phosphorylation of Rb can affect cell adhesion by regulating E-cadherin. Introducing p39 into Rb hypo-phosphorylated cell line induced an increase in phosphorylation of Rb residues. Furthermore, the CDK5-p39-Rb axis might point to the explanation and prediction of the metastatic phenotype in lung cancer. Citation Format: Jaileene Perez-Morales, Darielys Mejias-Morales, Bryan Torres-Collazo, Harry Negron-Pagan, Pedro Santiago-Cardona. A Rb phosphorylation code associated with lung cancer metastasis [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 2845. doi:10.1158/1538-7445.AM2017-2845