Targeted Therapy for CNS Disease in NSCLC: Brain-Penetrant TKIs, Resistance Mechanisms, and Rational Combinations

CNS metastases represent one of the most devastating complications of non-small-cell lung cancer (NSCLC), affecting up to 50% of patients during their disease course and historically associated with poor prognosis due to the limited penetrance of conventional systemic therapies across the blood–brain barrier (BBB). The emergence of brain-penetrant tyrosine kinase inhibitors (TKIs) has transformed the treatment landscape, demonstrating meaningful intracranial activity in molecularly defined patient subgroups. However, acquired CNS-specific resistance remains a critical and unresolved challenge, underscoring the need for deeper mechanistic understanding and novel therapeutic strategies.This Research Topic aims to consolidate and advance translational and clinical knowledge on the management of CNS disease in NSCLC, with a particular focus on the following areas:Molecular design, pharmacokinetic optimization, and BBB penetrance of next-generation TKIsOn-target resistance mutations and bypass pathway activation driving CNS progressionBiomarker-guided patient selection and intracranial response assessmentRational combination strategies, including TKIs with anti-angiogenics, immunotherapy, or radiotherapyTumor-intrinsic and microenvironmental factors shaping CNS-specific drug responseClinical sequencing strategies and real-world outcomes in patients with intracranial diseaseWe welcome original research articles, systematic reviews, meta-analyses, and expert opinion pieces that address these themes from translational, pharmacological, and clinical perspectives. Contributions that integrate molecular profiling with clinical outcomes to inform therapy selection and improve survival and quality of life in this patient population are particularly encouraged. Topic editors: Ira Ida Skvortsova Source: https://www.frontiersin.org/research-topics/82879/targeted-therapy-for-cns-disease-in-nsclc-brain-penetrant-tkis-resistance-mechanisms-and-rational-combinations