Provided herein are compositions and methods for treating, inhibiting and/or reducing the severity of neuroblastoma, small cell lung cancer (SCLC), large cell neuroendocrine cancer (LCNEC), large-cell carcinoma (LCC), squamous cell carcinoma (SqCC), and/or adenocarcinoma (AC) in subjects in need thereof. The methods include providing an agent that inhibits expression or activity of ONECUT2 and administering a therapeutically effective amount of the agent so as to treat, inhibit and/or reduce the severity of neuroblastoma, small cell lung cancer (SCLC), large cell neuroendocrine cancer (LCNEC), large-cell carcinoma (LCC), squamous cell carcinoma (SqCC), and/or adenocarcinoma (AC) in the subject.