HDGF and cancer: In addition, our strategy to identify sensitizing and protective gene pairs led to the discovery of novel combinatorial targets with clinical relevance, especially for the drug regimen of cilengitide + linsitinib and genotype combination of HDGF-+ LGR5-, which were found to be potent in overcoming MAPKi resistance in multiple cancer cells, which provided novel biological insights into a responsive protein complex formation mechanism that can adapt cancer cells to environmental stress.