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

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.

GZ17-6.02 and Pemetrexed Interact to Kill Osimertinib-Resistant NSCLC Cells That Express Mutant ERBB1 Proteins

“…Osimertinib is a relatively specific inhibitor of mutant active forms of ERBB1 and is, at present, the standard of care therapeutic. As with all targeted drugs in cancer, eventually NSCLC cells become osimertinib resistant, with diverse mechanisms, including gain of additional ERBB1 mutations or activation of other receptor tyrosine kinases such as c-MET and FGFRs (15)(16)(17)(18). Overcoming osimertinib resistance remains an important area for the developmental cancer therapeutics field in NSCLC.…”

Value of c-MET and Associated Signaling Elements for Predicting Outcomes and Targeted Therapy in Penile Cancer

“…Blockade of c-MET promoted a reduction in cell growth and proliferation in their analysis. Similarly, Zhu et al reported on the augmented expression of c-MET in non-small cell lung cancer cell lines with osimertinib resistance as compared to sensitive ones [ 36 ]. Treating resistant cells with the c-MET inhibitor capmatinib reduced EMT and self-renewal ability as well as promoting cell re-sensitization to osimertinib.…”

A novel gene signature based on the hub genes of COVID-19 predicts the prognosis of idiopathic pulmonary fibrosis

“…Inhibiting the classical NF-κB signaling pathway blocks growth hormone (GH) or insulin-like growth factor (IGF-1) signaling, suppresses cell proliferation, and suppresses bone morphogenetic protein 2 (BMP2) expression, thereby promoting apoptosis (Jimi et al, 2019). Most importantly, these three genes were all involved a lot in the inflammatory response (Zhang Z. et al, 2021;Zhu et al, 2021;Li et al, 2022), stating that inflammatory response was a main regulated pathway in IPF and these three genes could modulate the pathological process of IPF through this pathway.…”