Drugging ERK1/2 in Cancer: A Glimpse of Small-Molecule Inhibitors.

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.

Unveiling and harnessing: the tumor microenvironment in RAS/MAPK pathway-targeted therapy

Rational combination strategies are outlined that simultaneously target the RAS/MAPK axis and key TME vulnerabilities, such as immunotherapy combinations, CAF reprogramming, and ECM normalization, to overcome stromal-mediated resistance and achieve deeper, more sustained clinical responses.

PDK1 signaling in cancer: Current status and future perspectives.

Casein Kinase 1 and CK2 as Therapeutic Targets in Cancer: Molecular Pharmacology, Toxicological Considerations, and Clinical Progress.

Casein kinase 1 (CK1) and casein kinase 2 (CK2) are highly conserved serine/threonine protein kinases that regulate multiple oncogenic signaling pathways involved in cancer progression, metastasis, and therapeutic resistance. Overexpression or dysregulation of CK1 and CK2 has been shown to contribute to the development and resistance of cancer to anticancer therapies. This review summarizes the molecular functions of CK1 and CK2 in cancer biology and evaluates the therapeutic potential, pharmacological development, and clinical progress of CK-targeted inhibitors. A structured literature search was performed using PubMed, Scopus, and Web of Science databases to identify studies published between 2000 and 2026 related to CK1/CK2 signaling, pharmacological inhibitors, toxicology, and clinical development. CK1 and CK2 are involved in the regulation of various oncogenic signaling pathways, including the Wnt/β-catenin, p53, nuclear factor kappa B, and phosphatidylinositol-3-kinase/protein kinase B signaling pathways, as well as genomic integrity pathways. Dysregulation of these kinases leads to the survival, proliferation, and resistance of cancer cells to anticancer therapies. Several CK inhibitors, including CX-4945 (Silmitasertib), CIGB- 300, IC261, D4476, SR-3029, and BTX-A51, have shown promising anticancer activity in various cancer models. Novel dual-therapy approaches targeting CK1/CK2-regulated pathways have further improved the therapeutic specificity and efficacy. CK-targeting therapies are an exciting approach and hold great promise for selectively targeting cancer-causing signaling pathways and advancing cancer precision medicine.

PIK3CA in Cancer: Structure, Biology, Alterations, and Actionability

Simple Summary PIK3CA is one of the most frequently altered cancer-related genes and has become an important focus of precision oncology. However, the biological and clinical implications of PIK3CA alterations vary considerably across tumor types, and translating this knowledge into effective treatments remains challenging. This review provides a comprehensive, updated, and comparative overview of PIK3CA biology, its molecular alterations across human cancers, their prognostic and therapeutic relevance, and the current development of treatments targeting the pathway activated by PIK3CA. We critically examine both established evidence and remaining limitations, including treatment toxicity and resistance, and discuss emerging therapeutic and molecular approaches. By bringing these different aspects together, we aim to provide oncologists and researchers with a practical framework for understanding the current state of the field, interpreting available evidence, identifying unresolved questions, and designing future clinical and translational studies.

Adaptive mechanisms and emerging cancer therapeutics for CDK2 inhibitors.