ALK receptor tyrosine kinase

Overview

ALK receptor tyrosine kinase is a receptor tyrosine kinase encoded by the ALK gene and is best known in medicine as a clinically important oncogenic target in several cancers, especially ALK-rearranged non-small cell lung cancer (NSCLC) and anaplastic large cell lymphoma. In normal biology, ALK is a membrane-associated signaling protein, but in cancer it is most often relevant through gene rearrangements/fusions that lead to constitutive kinase activation and downstream proliferative and survival signaling.

Because ALK-driven tumors can be highly dependent on this signaling axis, ALK has become a major target for ALK-tyrosine kinase inhibitors (TKIs) such as crizotinib, alectinib, and lorlatinib. These agents have transformed treatment of ALK-positive NSCLC, including disease with central nervous system involvement, but resistance remains a major clinical challenge. Recent research also continues to use ALK status as a diagnostic and stratification marker in other tumors, including inflammatory myofibroblastic tumor and anaplastic large cell lymphoma.

Focus of Latest Publications

Recent publications on ALK receptor tyrosine kinase have focused heavily on ALK-driven non-small cell lung cancer, particularly the use of ALK-targeted tyrosine kinase inhibitors and related resistance mechanisms. Several studies examined clinical and translational questions around alectinib, lorlatinib, gilteritinib, and entrectinib, including first-line treatment strategies, induction therapy in stage III disease, and approaches to overcome resistance to second-generation ALK inhibitors. One exploratory study also assessed immune-related gene expression profiling in ALK-rearranged NSCLC to better characterize the tumor microenvironment and its relationship to alectinib efficacy.

A recurring theme is therapeutic resistance and how it may be modulated. In ALK-rearranged NSCLC, gilteritinib was reported to inhibit H2228/Al cell growth, induce apoptosis, reduce ALK protein levels, and overcome alectinib resistance in vitro and in a nude mouse xenograft model. The proposed mechanism involved inhibition of PD-L1 and CD8 co-expression. Another study evaluated the effects of nicardipine on entrectinib metabolism in vitro and in rats, reflecting interest in drug–drug interactions involving a multi-target TKI that includes ALK among its targets. A cost-effectiveness analysis also compared lorlatinib with alectinib as first-line therapy for ALK-positive advanced NSCLC in Italy, highlighting the continuing clinical evaluation of ALK inhibitors beyond efficacy alone.

Beyond lung cancer, ALK was investigated in other disease contexts and as a molecular marker. In anaplastic large cell lymphoma affecting the oral cavity, ALK protein expression was reported in two of three cases, consistent with the role of ALK gene fusions in subclassification of this lymphoma. In Parkinson’s disease, lorlatinib was studied as an ALK-specific inhibitor in an MPTP mouse model and was found to improve motor function, attenuate dopaminergic neuronal loss, suppress ALK phosphorylation, and reduce microglial and astrocytic activation, proinflammatory cytokine expression, oxidative stress, and blood–brain barrier disruption. These findings suggested a role for ALK-mediated neuroinflammation in the model.

Additional work extended ALK targeting into drug development and preclinical oncology. A study on modular silicon-containing pharmacophores reported the identification of sila-protein degraders, including a SiD-conjugated ALK degrader that showed significant tumor-suppressive activity in an ALK-positive H3122 xenograft model. Another study of induction alectinib or crizotinib for stage III ALK-fusion NSCLC with 4-year follow-up addressed the role of ALK-targeted induction therapy in locally advanced disease. Together, these publications show ALK receptor tyrosine kinase being studied as a therapeutic target, resistance marker, and disease-associated biomolecule across oncology and neuroinflammation.

Key Publications

• NEWJun [Translated article] Real world outcomes of first-line pembrolizumab in metastatic non-small-cell lung cancer. (Farmacia hospitalaria : organo oficial de expresion cientifica de la Sociedad Espanola de Farmacia Hospitalaria, 2026, PMID 42285782): "To describe the effectiveness and safety of pembrolizumab in routine clinical practice as first-line treatment for advanced/metastatic non-small cell lung cancer (NSCLC) with PD-L1 expression ≥50% and without EGFR or ALK alterations."
• Jun Evaluation of the Effects of Nicardipine on Entrectinib Metabolism in vitro and in Rats. (European journal of drug metabolism and pharmacokinetics, 2026, PMID 42230445): "Entrectinib, a multi-target tyrosine kinase inhibitor (TKI) against TRK, ROS1, and ALK, is clinically approved for genetically-defined solid tumors."
• May Oral manifestations of anaplastic large cell lymphoma: clinicopathological features and main immunophenotypic findings of 3 cases. (Journal of hematopathology, 2026, PMID 42213355): "Their subclassification relies on the presence or absence of Anaplastic Lymphoma Kinase (ALK) gene fusions and other molecular alterations."
• May Lorlatinib protects dopaminergic neurons by inhibiting ALK-mediated neuroinflammation in a mouse model of Parkinson's disease. (Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 2026, PMID 42208344): "Anaplastic lymphoma kinase (ALK) has recently emerged as a therapeutic target for inflammatory and immune disorders; however, its role in neuroinflammation and PD remains unclear."
• May Gilteritinib overcomes second‑generation TKIs resistance in ALK‑rearranged non‑small‑cell lung cancer by inhibiting PD‑L1 and CD8 co‑expression. (International journal of molecular medicine, 2026, PMID 42059267): "The present study investigated how gilteritinib overcomes resistance to second-generation tyrosine kinase inhibitors in anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC), providing new theoretical support for NSCLC treatment."
• Apr Cost-effectiveness analysis of lorlatinib as first-line treatment for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer in Italy. (Journal of medical economics, 2026, PMID 42043888): "Lorlatinib is a third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) with high central nervous system penetration and activity against resistance mutations."
• May Bringing Silicon to Drugs: Modular Construction of Sila-Pharmacophores for the Development of Target Protein Degraders. (Journal of the American Chemical Society, 2026, PMID 42024006): "Notably, we observed significant tumor-suppressive activity of a SiD-conjugated ALK degrader in a xenograft model using the H3122 cell line (ALK-positive), highlighting the therapeutic potential of sila-pharmacophores."
• Jun Immune-related gene expression profiling and alectinib efficacy for patients with ALK-Rearranged non-small cell lung cancer: exploratory analysis of a prospective observational study. (Lung cancer (Amsterdam, Netherlands), 2026, PMID 42013562): "The development of resistance to anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and a poor response to immune checkpoint inhibitors (ICIs) remain challenges in ALK-rearranged non-small cell lung cancer (NSCLC)."
• May Induction alectinib or crizotinib for stage III NSCLC harboring ALK fusion: A study with 4-year follow-up. (Chinese medical journal, 2026, PMID 41139663): "Despite increased response and long-term benefit of anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC) harboring ALK -fusion, the role of induction ALK-TKIs in locally advanced NSCLC remained poorly investigated."