Targeting MAPK Pathway in Cancer

Mitogen-activated protein kinase (MAPK) signaling cascade is fundamental in regulating cellular proliferation and differentiation, cell survival as well as cell death via apoptosis. Disruption in MAPK signaling cascade at any point can lead to evasion of apoptosis and unchecked cell growth and proliferation leading to oncogenesis. This narrative review describes MAPK pathway dysregulation, their therapeutic targets, and resistance mechanisms. The therapeutic targeting of MAPK pathway is complex owing to dual context dependent roles of several kinases in the signaling cascade. Despite therapeutic effectiveness of MAPK inhibitors, cancers cells develop chemoresistance that needs to be targeted via bypassing several molecular signaling points, pairing of MAPK inhibitors with multiple immune agents and targeting MAPK pathway downstream of ERK to prevent its reactivation mechanisms using combination therapies, downstream signaling regulators and PROTACs. Additionally, MAPK mediated regulation of ferroptosis is a novel oncological therapeutic targeting strategy for controlling tumor progression. The emerging therapies targeting MAPK pathway should be designed considering these crosstalks, compensatory signaling mechanism activation and the impact of tumor microenvironment.