Overexpression of PARP1 and enhancer of zeste homolog 2 (EZH2) has been identified in an integrated analysis of multiple proteins involved in intracellular signaling pathways in small cell lung cancer (SCLC) cell lines. The knockdown of PARP1 and EZH2 abrogated SCLC growth. These findings provide the basis for novel predictive markers and new treatment strategies in SCLC, for which there is now a paucity of available therapies.