Non-small cell lung cancer (NSCLC) is a leading cause of cancer death in the US and worldwide. In this application, we will study the contribution of the promyelocytic leukemia tumor suppressor (PML), casein kinase 2 (CK2), and oncogenic K-RAS (onc-K-RAS) to the pathogenesis of this disease. In addition, we will test in mouse models of lung cancer whether pharmacological inhibition of CK2 has a significant anti-tumor effect. PML, initially identified as a component of the PML-RAR1 of acute promyelocytic leukemia, plays a critical role in multiple tumor suppressive functions such as induction of oncogene induced replicative senescence (OIS), apoptosis, and neoangiogenesis. We have determined that: 1. PML is frequently lost in NSCLC and other human tumors due to aberrant ubiquitination triggered by direct phosphorylation by CK2, an oncogenic protein kinase;2. CK2 inhibitors display PML dependent anti-tumor properties in xenograft models;3. Pml loss disables the OIS response leading to tumor progression in a mouse NSCLC model initiated by onc-K-Ras. These observations imply that: 1. PML constrains inappropriate cell proliferation, acting as a bona fide tumor suppressor in vivo;2. upregulation of CK2 kinase activity contributes to cancer initiation and progression through a mechanism that involves aberrant PML ubiquitination and degradation. We propose that a better understanding of the cellular networks controlling OIS will be instrumental for the development of novel anti-cancer therapies. For example, the identification of the mechanisms controlling PML tumor suppressive activity, protein stability and catabolism will provide the framework for the development of novel targeted drugs. In this regards, CK2 inhibitors are expected to exert an anti-tumor effect by restoring PML protein levels within cancer cells and inducing and OIS response. We will address these hypotheses by identifying the mechanisms that mediate PML tumor suppressive function. In addition, we will determine the functional significance of PML loss in a model of non-small cell lung cancer initiated by onc-K-Ras. Finally, we will test the anti-tumor properties of specific inhibitors of CK2 in vivo in mouse models of NSCLC. These studies will shed light on the mechanisms leading to NSCLC tumorigenesis and will provide the framework for the development of novel therapeutic approaches for this devastating disease.

Public Health Relevance

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death. Novel therapeutic strategies are urgently needed. With this proposal, we are planning to move toward this goal by gaining a better understanding of the molecular networks that oppose cancer formation. We will characterize the tumor suppressive properties of the promyelocytic tumor suppressor (PML) in NSCLC. In addition, we will test whether PML protein restoration through inhibition of casein kinase 2, an oncogenic protein kinase that contributes to NSCLC tumorigenesis, leads to an antitumor effect in vivo. We will perform these experiments following an integrated strategy that will utilize cellular systems, a faithful mouse model of lung cancer NSCLC and a unique set of novel drugs. This work will provide the framework for the development of a novel strategy for the treatment of this devastating disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Molecular Pathobiology Study Section (CAMP)
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Yassin, Rihab R,
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University of Texas Sw Medical Center Dallas
Internal Medicine/Medicine
Schools of Medicine
United States
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Rabellino, Andrea; Andreani, Cristina; Scaglioni, Pier Paolo (2017) The Role of PIAS SUMO E3-Ligases in Cancer. Cancer Res 77:1542-1547
Tang, Ke-Jing; Constanzo, Jerfiz D; Venkateswaran, Niranjan et al. (2016) Focal Adhesion Kinase Regulates the DNA Damage Response and Its Inhibition Radiosensitizes Mutant KRAS Lung Cancer. Clin Cancer Res 22:5851-5863
Rabellino, Andrea; Melegari, Margherita; Tompkins, Van S et al. (2016) PIAS1 Promotes Lymphomagenesis through MYC Upregulation. Cell Rep 15:2266-2278
Constanzo, Jerfiz D; Tang, Ke-Jing; Rindhe, Smita et al. (2016) PIAS1-FAK Interaction Promotes the Survival and Progression of Non-Small Cell Lung Cancer. Neoplasia 18:282-293
Constanzo, Jerfiz D; Deng, Mi; Rindhe, Smita et al. (2016) Pias1 is essential for erythroid and vascular development in the mouse embryo. Dev Biol 415:98-110
Schuster, Katja; Venkateswaran, Niranjan; Rabellino, Andrea et al. (2014) Nullifying the CDKN2AB locus promotes mutant K-ras lung tumorigenesis. Mol Cancer Res 12:912-23
Konstantinidou, Georgia; Ramadori, Giorgio; Torti, Francesca et al. (2013) RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas. Cancer Discov 3:444-57
Scaglioni, Pier Paolo; Rabellino, Andrea; Yung, Thomas M et al. (2012) Translation-dependent mechanisms lead to PML upregulation and mediate oncogenic K-RAS-induced cellular senescence. EMBO Mol Med 4:594-602
Rabellino, Andrea; Carter, Brandon; Konstantinidou, Georgia et al. (2012) The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA. Cancer Res 72:2275-84
Naina, Harris V; Levitt, Daniel; Vusirikala, Madhuri et al. (2011) Successful treatment of relapsed and refractory extramedullary acute promyelocytic leukemia with tamibarotene. J Clin Oncol 29:e534-6