Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead t...Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC. Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines. Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all ;NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation. Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.展开更多
基金Work in Dr.Rosell’s laboratory is partially supported by a grant from La Caixa Foundationan Instituto de Salud Carlos III grant(RESPONSE,PIE16/00011,PI14/01678)+1 种基金a Marie Skłodowska-Curie Innovative Training Networks European Grant(ELBA No 765492)and a Spanish Association Against Cancer(AECC)grant(PROYE18012ROSE).
文摘Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds, which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC. Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses, and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and combined with osimertinib in five EGFR-mutation positive NSCLC cell lines. Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3) as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all ;NSCLC cell lines investigated. Among the EGFR-mutation positive cell lines examined, the H1975 and PC9 cell lines had the highest PIM1 and STAT3 mRNA expression. The combination decreased the osimertinib-induced STAT3 phosphorylation. Conclusion: This study provides a short review on PIM kinases, and shows our results of combined PIM and EGFR inhibition in EGFR-mutation positive NSCLC cell lines. The combination was moderately synergistic but decreased STAT3 phosphorylation, an important signaling node in therapy resistance.
