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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Respiratory Pharmacology
Volume 15 - 2024 | doi: 10.3389/fphar.2024.1502165
This article is part of the Research Topic Therapeutic Advances in Lung Cancer and Chronic Inflammatory Lung Disease View all 18 articles

CD146 promotes resistance of NSCLC brain metastases to pemetrexed via the NF-κB signaling pathway

Provisionally accepted
Hao Qu Hao Qu 1Yan Fang Yan Fang 1Feng Zhang Feng Zhang 2Wenwen Liu Wenwen Liu 2Shengkai Xia Shengkai Xia 2Wenzhe Duan Wenzhe Duan 2Kun Zou Kun Zou 1*
  • 1 First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning Province, China
  • 2 Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China

The final, formatted version of the article will be published soon.

    Abstract Pemetrexed is a first line drug for brain metastases from lung cancer, either as monotherapy or combined with other drugs. The frequent occurrence of initial and acquired resistance to pemetrexed results in limited treatment effectiveness in brain metastases. CD146 was recently found to play important roles in chemoresistance and tumor progression. However, the underlying mechanisms of CD146’s effects in pemetrexed resistance remain undefined. Sensitivity to pemetrexed was assessed with a preclinical brain metastasis (BM) model based on lung adenocarcinoma PC9 cells. The role and mechanism of CD146 in pemetrexed resistance in nonsmall cell lung cancer (NSCLC) brain metastasis were explored in vitro and in vivo. A subpopulation of brain metastatic cells derived from progenitor PC9 cells (PC9BrMS) was significantly resistant to pemetrexed. CD146 levels were significantly increased in pemetrexedresistant brain metastases, while CD146 inhibition suppressed pemetrexed resistance in BM cells. Mechanistically, CD146 mediated pemetrexed resistance in brain metastatic cells by promoting DNA damage repair, maintaining normal cell cycle progression, and regulating the NFΚB pathway to counter apoptosis, and these effects was based on increased DNA damage, cell cycle arrest, and occurrence of apoptosis after CD146 inhibition as well as the reemergence of pemetrexed resistance after CD146 restoration. Thus CD146 might be targeted in clinic to overcome pemetrexed resistance in brain metastases from NSCLC.

    Keywords: CD146, brain metastasis, chemotherapeutic resistance, pemetrexed, lung cancer

    Received: 26 Sep 2024; Accepted: 16 Dec 2024.

    Copyright: © 2024 Qu, Fang, Zhang, Liu, Xia, Duan and Zou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Kun Zou, First Affiliated Hospital, Dalian Medical University, Dalian, 116011, Liaoning Province, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.