NTRK2 promotes malignant progression and paclitaxel resistance of lung adenocarcinoma through targeting MYC/ABCF1 axis.

Lung adenocarcinoma (LUAD) is the most prevalent histological subtype of lung cancer, and the development of chemoresistance often leads to tumor recurrence and metastasis. Neurotrophic receptor tyrosine kinase 2 (NTRK2) has been implicated in tumorigenesis and chemotherapy resistance, but its precise role in LUAD and contribution to paclitaxel resistance remain unclear. In this study, we found that NTRK2 expression was significantly upregulated in LUADs compared with paired noncancerous tissues and was further elevated in samples from patients who experienced recurrence following paclitaxel-based chemotherapy. Functional assays demonstrated that NTRK2 knockdown markedly inhibited the malignant phenotypes of LUAD cells in vitro and significantly restored the sensitivity of LUAD cells to paclitaxel. Conversely, NTRK2 overexpression promoted cell proliferation, colony formation, and reduced responsiveness to paclitaxel. Consistently, in vivo xenograft experiments revealed that NTRK2 knockdown suppressed tumor growth and enhanced the antitumor efficacy of paclitaxel. Mechanistically, NTRK2 activated the MAPK/ERK and PI3K/AKT signaling pathways, leading to the upregulation of MYC, which in turn directly activated the transcription of ATP-binding cassette subfamily F member 1 (ABCF1), thereby promoting LUAD progression and paclitaxel resistance. Collectively, our findings identify NTRK2 as a critical oncogenic driver that confers chemoresistance by activating the NTRK2/MYC/ABCF1 signaling axis. This study provides new mechanistic insights into the regulation of paclitaxel resistance in LUAD and highlights NTRK2 and its downstream effectors as promising therapeutic targets for overcoming chemoresistance.