https://doi.org/10.1016/j.apsb.2025.06.002
This new article publication from Acta Pharmaceutica Sinica B, discusses key challenges in targeted treatment of brain metastatic non-small cell lung cancer.
Over the past two decades, marked progress has been made in treating non-small cell lung cancer (NSCLC) patients with EGFR-, ALK-, ROS1- and KRASG12C-targeted inhibitors. NSCLC patients very often develop brain metastases. Despite the continuous development of newer and better inhibitors, the survival outcomes of NSCLC patients with brain metastases remain significantly worse than those of patients without. The main challenges in these pharmacotherapies are the development of resistance mutations, and, potentially, the presence of the blood–brain barrier (BBB). The outcomes of clinical studies show the improved efficacy of later-generation targeted inhibitors. The increase in progression free survival (PFS) in patients treated with these later-generation inhibitors is largely attributed to their efficacy against multiple resistance mutations, and possibly due to enhanced brain penetration. This review explores the different aspects hindering the targeted treatment of NSCLC and especially of brain metastases, focusing on recent clinical trials and emerging resistance mutations and the influence of the BBB on the efficacy of EGFR, ALK, ROS1 and KRASG12C inhibitors. The role of the ABCB1 and ABCG2 drug transporters in differential efflux of the targeted drugs at the BBB is also discussed, since preclinical studies indicate that they may reduce the efficacy of transported inhibitors.
Keywords: ABC transporters, Blood–brain barrier, Brain metastases, NSCLC, Drug resistance, Targeted therapies
Graphical Abstract: available at https://ars.els-cdn.com/content/image/1-s2.0-S2211383525003995-ga1_lrg.jpg
Advances in targeted therapy for NSCLC brain metastases and how acquired resistance mutations and the blood–brain barrier might interfere with the efficacy of targeted inhibitors.
# # # # # #
The Journal of the Institute of Materia Medica, the Chinese Academy of Medical Sciences and the Chinese Pharmaceutical Association.
For more information please visit https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/
Editorial Board: https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/editorial-board
APSB is available on ScienceDirect (https://www.sciencedirect.com/journal/acta-pharmaceutica-sinica-b).
Submissions to APSB may be made using Editorial Manager® (https://www.editorialmanager.com/apsb/default.aspx).
CiteScore: 24.3
Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy)
JIF without self-citation: 13.8
ISSN 2211-3835
# # # # #
Jamie Rijmers, Maria C. Lebre, Jos H. Beijnen, Alfred H. Schinkel, Resistance mutations and the blood–brain barrier: Key challenges in targeted treatment of brain metastatic non-small cell lung cancer, Acta Pharmaceutica Sinica B, Volume 15, Issue 8, 2025, Pages 3833-3851, ISSN 2211-3835, https://doi.org/10.1016/j.apsb.2025.06.002
Journal
Acta Pharmaceutica Sinica B