Novel therapeutic strategies targeting bypass pathways and mitochondrial dysfunction to combat resistance to RET inhibitors in NSCLC

医学 癌症研究 生物 药理学
作者
Aya Shiba‐Ishii,Takayuki Isagawa,Toshihiro Shiozawa,Naoko Mato,Tomoki Nakagawa,Yurika Takada,Kanon Hirai,Jeongmin Hong,Anri Saitoh,Norihiko Takeda,Toshiro Niki,Yoshinori Murakami,Daisuke Matsubara
出处
期刊:Biochimica Et Biophysica Acta: Molecular Basis Of Disease [Elsevier]
卷期号:1870 (6): 167249-167249
标识
DOI:10.1016/j.bbadis.2024.167249
摘要

RET fusion is an oncogenic driver in 1–2 % of patients with non-small cell lung cancer (NSCLC). Although RET-positive tumors have been treated with multikinase inhibitors such as vandetanib or RET-selective inhibitors, ultimately resistance to them develops. Here we established vandetanib resistance (VR) clones from LC-2/ad cells harboring CCDC6-RET fusion and explored the molecular mechanism of the resistance. Each VR clone had a distinct phenotype, implying they had acquired resistance via different mechanisms. Consistently, whole exome-seq and RNA-seq revealed that the VR clones had unique mutational signatures and expression profiles, and shared only a few common remarkable events. AXL and IGF-1R were activated as bypass pathway in different VR clones, and sensitive to a combination of RET and AXL inhibitors or IGF-1R inhibitors, respectively. SMARCA4 loss was also found in a particular VR clone and 55 % of post-TKI lung tumor tissues, being correlated with higher sensitivity to SMARCA4/SMARCA2 dual inhibition and shorter PFS after subsequent treatments. Finally, we detected an increased number of damaged mitochondria in one VR clone, which conferred sensitivity to mitochondrial electron transfer chain inhibitors. Increased mitochondria were also observed in post-TKI biopsy specimens in 13/20 cases of NSCLC, suggesting a potential strategy targeting mitochondria to treat resistant tumors. Our data propose new promising therapeutic options to combat resistance to RET inhibitors in NSCLC.
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