Targeting the ERK/MAPK Pathway in Cancer: Oncogenic Mechanisms, Therapeutic Resistance, and Emerging Gene-Based Strategies

<jats:p>The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade is a central effector of receptor tyrosine kinase-RAS-RAF-MEK signalling and a major therapeutic axis in oncology. Persistent ERK output supports cell-cycle progression, survival, invasion, angiogenesis and tumour-microenvironment remodelling, but pathway dependence is shaped by tumour lineage, driver class, co-mutations and feedback architecture. This narrative review uses a mechanism-first, lineage-specific framework to compare ERK-driven oncogenesis in melanoma, lung cancer and colorectal cancer and to explain why similar pathway alterations can produce different therapeutic responses. Resistance is organised into three interacting themes. Rapid adaptive resistance follows relief of negative feedback and receptor-RAS rebound. Acquired genetic resistance restores MAPK signalling through RAS activation, RAF dimerisation, BRAF amplification or splice variants, and MEK or ERK alterations. Tumours may also survive through parallel PI3K-AKT-mTOR signalling, lineage plasticity, drug-tolerant persister states and stromal support. The review further examines the context-dependent relationship between tumour-intrinsic ERK signalling, immune exclusion and T-cell function, which complicates combinations with immune checkpoint blockade. Clinical evidence supports BRAF-MEK combinations in molecularly selected cancers and combined BRAF-EGFR blockade in BRAF V600E colorectal cancer. RNA interference, CRISPR screening, single-cell and spatial profiling, and artificial-intelligence-assisted prediction are evaluated according to their translational maturity. The main conclusion is that durable ERK/MAPK control will require lineage-aware patient selection, longitudinal resistance monitoring, and mechanism-matched combination therapy rather than uniform pathway inhibition.</jats:p>