Abstract 1840: Nedd9 controls glycolysis and autophagy in non-small cell lung cancer (NSCLC)

Non-small cell lung cancer (NSCLC) has a low survival rate, with metastasis contributing to the vast majority of deaths. Elevated expression of the protein NEDD9 has been reported in a large subset of lung cancers and other malignancies as a promotor of aggressive phenotypes and drug resistance. NEDD9 exerts these pro-metastatic roles by serving as a scaffold for intermediates in the integrin and receptor tyrosine kinase signaling cascades, and other pathways, with NEDD9 knockdown impairing cell migration, motility, and growth. Because scaffolds act by assembling functional complexes in precise stoichiometries, there are cases where both loss and gain result in loss of function. Through analysis of TCGA data, we identified a subset of human NSCLC with low levels of NEDD9 expression, associated with lower overall survival. Therefore, in this study, we for the first time assessed the consequences of a constitutive null genotype for Nedd9 for cancer formation in the 129S/Sv-Kras tm3Tyj /Trp53 tm1Brn (KP) murine model of NSCLC. Unexpectedly, we found deletion of Nedd9 (in a KPN genotype) significantly accelerated NSCLC tumorigenesis and enhanced tumor invasion. Proteomic analysis of KPN versus KP tumors confirmed these more aggressive phenotypes occurred in spite of depressed activity of the pro-proliferative Nedd9 partners Src and Fak, and surprisingly, suggested depressed expression of activity of enzymes involved in glycolysis in KPN tumors. Functional exploration confirmed a similar protein expression and activity profile, and strongly reduced glycolytic capacity, in multiple human NEDD9-depleted NSCLC cell lines, for the first time demonstrating NEDD9 regulation of glycolysis through control of hexokinase II (HK2) and other enzymes acting upstream of PGK. Compensating for these negative effects of Nedd9 loss during in vivo tumorigenesis, NSCLC tumors arising in KPN mice additionally activated AMPK, causing significantly elevated levels of autophagy, with both aggressive tumor growth and autophagy reduced by the SRC inhibitor dasatinib. Such compensatory activation of autophagy did not occur in cell lines with depleted NEDD9, distinguishing in vitro and in vivo tumor cell signaling response to NEDD9 loss. In sum, these data for the first time identify and define a role for the pro-metastatic protein NEDD9 in control of glycolytic metabolism in NSCLC setting, and establish a mechanism for this control. This data should be useful in guiding selection of patients for specific therapies targeting metabolic pathways. Citation Format: Alexander Y. Deneka, Anna Nikonova, Meghan Kopp, Anna Gaponova, Anna Kiseleva, Harvey Hensley, Erica Golemis. Nedd9 controls glycolysis and autophagy in non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1840.