Abstract For decades, lung cancer has been a leading cause of death in the U.S., mainly due to oncogenic signaling pathways activated by carcinogens such as smoking. Various carcinogens induce EGFR/RAS/MAPK signaling that is critical in the development of lung cancer. In particular, constitutive activation of extracellular signal-regulated kinase 2 (ERK2) is observed in many lung cancer patients, and therefore developing compounds capable of targeting ERK2 against lung carcinogenesis will be beneficial to these patients. Herein, we examined the therapeutic effects of catechol (also known as pyrocatechol or 1,2-dihydroxybenzene), a naturally occurring chemical in many foods such as apple, banana, apricot, grape, plum, avocado and mushroom. Co-crystallography results suggested that ERK2 is a direct target of catechol. In agreement with the co-crystallography result, catechol was confirmed to inhibit ERK2 kinase activity in vitro. Catechol inhibited anchorage-independent KP2 and H460 lung cancer cell growth in a dose-dependent manner. Phosphorylation of c-Myc, a substrate of ERK2, was reduced in catechol-treated lung cancer cells compared to untreated controls. Decreased c-Myc phosphorylation resulted in its reduced protein stability and subsequent down-regulation of total c-Myc levels. Treatment with catechol induced G1 cell cycle arrest and resulted in a decrease of G1 phase related proteins, CDK2 and cyclin D1. In vivo study results also revealed that catechol inhibited growth of KP2 and H460 xenograft tumors. Phosphorylation levels of c-Myc were also strongly decreased by catechol treatment in vivo. Taken together, we have shown that catechol exerts inhibitory effects on the ERK2/c-Myc signaling axis in lung cancer cells to reduce tumor growth in vitro and in vivo. These findings suggest that catechol, a natural small molecule, possesses potential as a novel therapeutic agent against lung carcinogenesis. Citation Format: Do Young Lim, Seung Ho Shin, Margarita Malakhova, Mee-Hyun Lee, Ann M. Bode, Zigang Dong. A natural small molecule, catechol, induces c-Myc degradation by directly targeting ERK2 in lung cancer in vitro and in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2601. doi:10.1158/1538-7445.AM2015-2601