2. Academic Validation
  3. Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer

Response and acquired resistance to MET inhibitors in de novo MET fusion-positive advanced non-small cell lung cancer

  • Lung Cancer. 2023 Apr:178:66-74. doi: 10.1016/j.lungcan.2023.01.017.
Jin Kang 1,  Qiu-Mei Deng 1,  Weineng Feng 2,  Zi-Hao Chen 1,  Jun-Wei Su 3,  Hua-Jun Chen 4,  Wen-Xian Wang 5,  Shirong Zhang 6,  Qian Wang 7,  Zexin Chen 8,  Wen-Zhao Zhong 9,  Chun-Wei Xu 10,  Jin-Ji Yang 11
Affiliations

Affiliations

  • 1 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China.
  • 2 Department of Head and Neck/Thoracic Medical Oncology, The First People's Hospital of Foshan, Foshan, Guangdong 528000, PR China.
  • 3 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China; Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080, PR China.
  • 4 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China.
  • 5 Department of Chemotherapy, Chinese Academy of Sciences University Cancer Hospital (Zhejiang Cancer Hospital), Hangzhou, Zhejiang 310022, PR China.
  • 6 Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Cancer Center, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310006, PR China.
  • 7 Department of Respiratory Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu 210029, PR China.
  • 8 Guangdong Research Center of Organoid Technology and Engineering, Guangzhou, Guangdong 510700, PR China.
  • 9 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China. Electronic address: 13609777314@163.com.
  • 10 Department of Respiratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing 210002, PR China. Electronic address: xuchunweibbb@163.com.
  • 11 Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China; Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, 106 Zhongshan 2nd Rd., Guangzhou, Guangdong 510080, PR China. Electronic address: yangjinji@gdph.org.cn.
PMID: 36806896 DOI: 10.1016/j.lungcan.2023.01.017
Abstract

Objectives: De novo mesenchymal-to-epithelial transition (MET) gene fusions in non-small cell lung Cancer (NSCLC) are a promising target for MET tyrosine kinase inhibitors (TKIs). We aimed to examine the response to targeted therapy with MET TKIs and resistance mechanisms in de novo MET fusion-positive NSCLC as these have not been comprehensively explored.

Materials and methods: We examined the MET fusions in 4,429 patients with advanced-stage NSCLC using targeted next-generation Sequencing and validated the results using RT-PCR. We analyzed cellular models harboring MET fusions and established a patient-derived Organoid (PDO) model.

Results: We identified 13 (0.29 %, 13/4429) patients with de novo MET fusions and found EphB4, THAP5, TNPO3, and DST as novel MET fusion partners. The most common concomitant gene with MET fusions was TP53 mutations. Among 12 patients receiving MET TKI treatment, two achieved stable disease, six achieved partial response, and four underwent progressive disease. An in vitro study showed that EPHB4-MET is a functional driver gene. MET inhibitors significantly inhibited the proliferation and phosphorylation of downstream STAT3, Akt, and ERK1/2 in EPHB4-MET overexpressing cells. Acquired MET D1228H/N or D1246N mutations were found in patients harboring MET fusions after acquiring resistance to MET TKIs. Tivantinib showed optimal suppression efficacy in a PDO model with an acquired MET D1228N mutation.

Conclusion: MET fusions occur in a rare subset of patients with NSCLC and represent a promising therapeutic target. MET secondary mutations D1228H/N or D1246N present the potential resistance mechanisms of MET inhibitors in patients with de novo MET fusions.

Keywords

EPHB4-MET; MET fusions; Non-small cell lung cancer; Tyrosine kinase inhibitors.

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