Thus, ERK pathway-targeted drug-induced PHLDA1/2 downregulation profoundly attenuated not only the efficacy of ERK pathway-targeted therapeutics, but also the additive anti-tumor effect of conventional chemotherapies (e.g., etoposide) when combined with such drugs (e.g., trametinib) by enhancing pro-survival AKT activity in the tumor cells. This evidence concerns the gene PHLDA1 and neoplasm.