Abstract PR01: Modeling Rb loss and pathway reactivation in lung adenocarcinoma

Abstract

Abstract Mutations in the Rb tumor suppressor pathway are a hallmark of cancer and a prevalent feature of lung adenocarcinoma. Additionally, recent clinical successes with cyclin dependent kinase inhibitors have reinvigorated interest in reactivating the Retinoblastoma (Rb) pathway to treat lung adenocarcinoma and other tumor types. Remarkably though, Rb’s role in suppressing lung adenocarcinoma remains unclear, and whether Rb pathway reactivation would be efficacious in this disease remains unknown. To model Rb pathway reactivation as treatment strategy in lung adenocarcinoma and to shed light on its role in this disease, we established an RbXTR allele that enables Cre-dependent inactivation of Rb in developing tumors, and allows Flp recombinase-inducible reactivation of Rb after tumors are established. In the KrasLox-Stop-Lox-G12D/+;p53flox/flox (KP) mouse model of lung adenocarcinoma, we show that Rb inactivation facilitates the bypass of two molecularly distinct barriers to tumor progression and dramatically accelerates malignant conversion and the development of metastatic disease. Although, in the presence of Rb, malignant conversion requires amplification of the Raf/Mek/Erk (MAPK) signaling pathway beyond that normally activated by the Kras oncogene, we find that this requirement is abrogated when Rb is inactivated. Mechanistically, we identified Cdk2 as an important effector downstream of amplified MAPK signaling and that this activity suppresses Rb’s ability to limit the adenoma-to-carcinoma transition. Importantly, inactivation of Cdk2 reduces cell proliferation in Rb wild-type cells and confers sensitivity to Cdk4/6 inhibition in both human and mouse lung adenocarcinoma cell lines were intrinsically resistant. Acquiring metastatic competency in Rb wild-type tumors is causally linked to epigenetic changes resulting in loss of lung lineage cell fate-determining transcription factors and concomitant derepression of factors normally restricted to embryonic cell types. However, inactivation of Rb uncouples the onset of metastatic competency from the loss of lung lineage factors, facilitates the early derepression of prometastatic factors, and significantly enhances metastatic proclivity. Finally, we demonstrate that reactivation of Rb in metastatic disease settings reprograms these tumors toward a less aggressive cell state and improves overall survival. Our study highlights an unappreciated role for Rb in regulating metastasis-promoting programs, and the potential of Rb restorative therapies to treat lung adenocarcinoma. Further, we suggest that a renewed investment in the development of specific Cdk2 inhibitors may be necessary for Rb pathway reactivation in certain cancer types. This abstract is also being presented as Poster A27. Citation Format: Travis Yates, Caroline Kim-Kiselak, Walter Wang, David M. Feldser. Modeling Rb loss and pathway reactivation in lung adenocarcinoma [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr PR01.