Thus, co-administration of bortezomib with ERK pathway inhibitors (e.g., trametinib) can maintain an elevated level of PHLDA1/2 expression in cancer cells, and greatly enhance the anti-tumor effects of ERK pathway-targeted drugs by disrupting the PHLDA1/2-mediated, cancer-specific aberrant signaling crosstalk between ERK and AKT (Supplementary Fig. 9h). The gene discussed is MAPK1; the disease is cancer.