1. MET inhibitor, capmatinib overcomes osimertinib resistance via suppression of MET/Akt/snail signaling in non-small cell lung cancer and decreased generation of cancer-associated fibroblasts
- Author
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Zhonghua Lv, Hua Jin, Hongshan Zheng, Lei Yu, Chenlong Li, Zhenzhe Li, Sibin Zhang, Jinsheng Xiong, Kaibin Zhu, Peng Liang, and Jixing Zhang
- Subjects
Aging ,Epithelial-Mesenchymal Transition ,Lung Neoplasms ,Cell ,Interleukin-1beta ,MET associated signaling ,non-small cell lung cancer (NSCLC) ,Vimentin ,cancer-associated fibroblasts (CAFs) ,Cancer-Associated Fibroblasts ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,medicine ,Humans ,Osimertinib ,Lung cancer ,Protein kinase B ,osimertinib resistance ,capmatinib ,Tumor microenvironment ,Acrylamides ,Aniline Compounds ,biology ,Chemistry ,Triazines ,Imidazoles ,Cell Biology ,Proto-Oncogene Proteins c-met ,medicine.disease ,medicine.anatomical_structure ,Drug Resistance, Neoplasm ,Benzamides ,Cancer research ,biology.protein ,Snail Family Transcription Factors ,Tyrosine kinase ,Proto-Oncogene Proteins c-akt ,Research Paper ,Signal Transduction - Abstract
Background Patients with non-small cell lung cancer (NSCLC) initially responding to tyrosine kinase inhibitors (TKIs) eventually develop resistance due to accumulating mutations in the EGFR and additional lesser investigated mechanisms such as the participation of the tumor microenvironment (TME). Methods Here, we examined the potential for MET inhibitor capmatinib for the treatment of osimertinib-resistant NSCLCs and normalizing the TME. Results We first established that HCC827 and H1975 cells showed increased resistance against osimertinib when co-cultured with CAFs isolated from osimertinib-resistant patients. Additionally, we showed that CAFs promoted epithelial-mesenchymal transition (EMT) and self-renewal ability in both HCC827 and H1975 cells. We subsequently found that both CAF-cultured HCC827 and H1975 showed a significantly higher expression of MET, Akt, Snail and IL-1β, which were associated with survival and inflammatory responses. These cells in turn, promoted the generation of CAFs from normal lung fibroblasts. Subsequently, we observed that the treatment of capmatinib resulted in the re-sensitization of CAF-co-cultured H1975 and HCC827 to osimertinib, in association with reduced EMT and self-renewal ability. MET-silencing experiment using siRNA supported the observations made with capmatinib while with a greater magnitude. MET-silenced cell exhibited a severely hindered expression of inflammatory markers, IL-1β and NF-κB; EMT markers, Snail and Vimentin, while increased E-cadherin. Finally, we demonstrated that the combination of capmatinib and osimertinib led to an increased tumor inhibition and significantly lower number of CAFs within the patient derived xenograft (PDX) model. Conclusion Taken together, our findings suggested that an increased MET/Akt/Snail signaling was induced between the NSCLC cells and their TME (CAFs), resulting in osimertinib resistance. Suppression of this pathway by capmatinib may bypass the EGFR activating mutation and overcomes osimertinib resistance by targeting both tumor cells and CAFs.
- Published
- 2021