Lung cancer is the leading cause of cancer mortality in the US and worldwide. Of the two main histopathological types of lung cancer, non-small cell lung cancer (NSCLC) - which includes adenocarcinoma (AC) and squamous cell carcinoma (SCC) - comprises approximately 85% of all lung cancer patients while small cell lung cancer (SCLC) makes up the remaining 15%. KRAS mutations are found in ~25% of lung adenocarcinomas (LUADs), EGFR mutations are seen in ~15% of LUADs, and the remaining are small percentages of other mutations. At present, the 5-year survival rate of lung cancer is <20%, thus, underscoring preventive strategies including smoking cessation and secondary preventive approaches for high-risk individuals with atypical lung nodules with hyperplasia and adenomas. ONC201 (TIC10) is a selective antagonist of dopamine receptor D2 that reduces cell proliferation and induces TNF-related apoptosis inducing ligand (TRAIL)-mediated apoptosis via integrated stress response activation and AKT/ERK inactivation. It is highly specific for cancer cells, having no effect on normal cells at concentrations that inhibit cancer cell growth. ONC201 is orally available and has demonstrated a favorable safety profile in rats and dogs, as well as in Phase 1 trials in advanced solid tumors. In the Phase 1 trials, ONC201 was administered at doses up to 625 mg once weekly for 3 weeks. No drug-related toxicities greater than grade 1 were reported, the dose was well tolerated, and displayed favorable pharmacokinetic properties in trial subjects. ONC201 is currently being tested in several Phase 2 trials (e.g., NCT03034200, NCT03295396, NCT03485729, NCT02525692, and NCT04055649). Preliminary studies with ONC201 have shown that ONC201 suppresses the lung tumor growth of A549 xenografts in SCID mice in a dose-dependent manner. Both the tested doses (10 and 50 mg/kg ONC201) did not affect the body weights of treated mice and significantly increased TRAIL and Death Receptor 5 (DR5) protein levels while inactivating Akt- Erk signaling. The purpose of this Task Order is to determine the potential clinical usefulness of ONC201 in preventing high risk LUAD in preclinical models.