Extracellular‐signal‐regulated kinase/mitogen‐activated protein kinase signaling as a target for cancer therapy: an updated review

Mitogen‐activated protein kinase (MAPK) signaling pathway is activated in a wide spectrum of human tumors, exhibiting cardinal oncogenic roles and sustained inhibition of this pathway is considered as a primary goal in clinic. Within this pathway, receptor tyrosine kinases such as epithelial growth factor receptor, mesenchymal–epithelial transition, and AXL act as upstream regulators of RAS/RAF/MEK/extracellular‐signal‐regulated kinase. MAPK signaling is active in both early and advanced stages of tumorigenesis, and it promotes tumor proliferation, survival, and metastasis. MAPK regulatory effects on cellular constituent of the tumor microenvironment is for immunosuppressive purposes. Cross‐talking between MAPK with oncogenic signaling pathways including WNT, cyclooxygenase‐2, transforming growth factor‐β, NOTCH and (in particular) with phosphatidylinositol 3‐kinase is contributed to the multiplication of tumor progression and drug resistance. Developing resistance (intrinsic or acquired) to MAPK‐targeted therapy also occurs due to heterogeneity of tumors along with mutations and negative feedback loop of interactions exist between various kinases causing rebound activation of this signaling. Multidrug regimen is a preferred therapeutic avenue for targeting MAPK signaling. To enhance patient tolerance and to mitigate potential adversarial effects related to the combination therapy, determination of a desired dose and drug along with pre‐evaluation of cancer‐type‐specific kinase mutation and sensitivity, especially for patients receiving triplet therapy is an urgent need. Highlights ● Mitogen‐activated protein kinase (MAPK) pathway consists of different kinases that their interactions promote cancer initiation, growth, and metastasis. ● Amplifications and mutations of up‐ and downstream kinases along with epigenetic silencing of kinase suppressors occur commonly in cancer and are associated with rebound MAPK activation and therapy resistance. Aberrant activation of MAPK pathway and therapy failure also occur due to existence of negative feedback loop of interactions between the kinases along with MAPK interactions with tumor promoting signaling pathways including transforming growth factor‐β, cyclooxygenase‐2, WNT, NOTCH, and particularly with phosphatidylinositol 3‐kinase. ● To make a durable anti‐tumor response, a preferred strategy is to use combination therapy (rather than monotherapy) using different kinase inhibitors along with chemo‐ and/or immunothe