Targeting MAPK Pathways in Skin, Thyroid, and Pancreatic Cancer: A Perspective on Synthetic Inhibitors and Natural Modulators.

Cancer frequently arises from the impaired functioning of the Mitogen-activated protein kinase (MAPK) signaling system, driven by mutation or overexpression of key signaling components. RAF, MEK, ERK, and KRAS inhibitors have significantly improved clinical outcomes, but efficacy is still restricted due to pathway reactivation, adaptive resistance, and signaling cross-talk. These limitations have led to the search for novel therapeutic approaches and molecular targets in the MAPK network. Melanoma, thyroid carcinoma, and pancreatic adenocarcinoma were selected because MAPK pathway alterations contribute to their pathogenesis and influence treatment response. This review examines the biological importance of MAPK signaling in these cancers and discusses MAPK-targeted therapies, mechanisms of resistance, and combination treatment options. It also addresses the expanding evidence on natural compounds that modulate MAPK- related signaling networks and reviews recent transcriptomic findings that have enhanced the identification of clinically relevant molecular targets. Additionally, MAP4K4 has been linked to tumor progression and metastasis, and poor clinical outcomes, indicating its potential as a therapeutic target for future clinical studies. The findings presented in this review suggest that combining transcriptomic evidence with molecular and pharmacological analyses could aid target prioritization and accelerate the development of targeted strategies for MAPK-driven malignancies.