| Added by | amaraver |
|---|---|
| Last modified by | informatique.ircm |
| Group name | EquipeAM |
| Item Type | Journal Article |
| Title | Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma |
| Creator | Bousquet Mur et al. |
| Author | Emilie Bousquet Mur |
| Author | Sara Bernardo |
| Author | Laura Papon |
| Author | Maicol Mancini |
| Author | Eric Fabbrizio |
| Author | Marion Goussard |
| Author | Irene Ferrer |
| Author | Anais Giry |
| Author | Xavier Quantin |
| Author | Jean-Louis Pujol |
| Author | Olivier Calvayrac |
| Author | Herwig P. Moll |
| Author | Yaël Glasson |
| Author | Nelly Pirot |
| Author | Andrei Turtoi |
| Author | Marta Cañamero |
| Author | Kwok-Kin Wong |
| Author | Yosef Yarden |
| Author | Emilio Casanova |
| Author | Jean-Charles Soria |
| Author | Jacques Colinge |
| Author | Christian W. Siebel |
| Author | Gilles Favre |
| Author | Luis Paz-Ares |
| Author | Antonio Maraver |
| Abstract | EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFRT790M and EGFRC797S. It is generally assumed that these secondary mutations render EGFR completely unresponsive to the inhibitors, but contrary to this, we uncovered here that gefitinib and osimertinib increased STAT3 phosphorylation (p-STAT3) in EGFRT790M and EGFRC797S tumoral cells. Interestingly, we also found that concomitant Notch inhibition with gefitinib or osimertinib treatment induced a p-STAT3-dependent strong reduction in the levels of the transcriptional repressor HES1. Importantly, we showed that tyrosine kinase inhibitor-resistant tumors, with EGFRT790M and EGFRC797S mutations, were highly responsive to the combined treatment of Notch inhibitors with gefitinib or osimertinib, respectively. Finally, in patients with EGFR mutations treated with tyrosine kinase inhibitors, HES1 protein levels increased during relapse and correlated with shorter progression-free survival. Therefore, our results offer a proof of concept for an alternative treatment to chemotherapy in lung adenocarcinoma osimertinib-treated patients after disease progression. |
| Publication | The Journal of Clinical Investigation |
| Volume | 130 |
| Issue | 2 |
| Pages | 612-624 |
| Date | 2020-02-03 |
| Journal Abbr | J Clin Invest |
| Language | eng |
| DOI | 10.1172/JCI126896 |
| ISSN | 1558-8238 |
| Library Catalog | PubMed |
| Extra | 00004 PMID: 31671073 PMCID: PMC6994195 |
| Tags | Acrylamides, Adenocarcinoma of Lung, Amino Acid Substitution, Aniline Compounds, Animals, corresponding, Drug Resistance, Neoplasm, Drug therapy, ErbB Receptors, first, first-last-corresponding, Gefitinib, last, Lung Neoplasms, Mice, Mice, Transgenic, Mutation, Missense, Neoplasm Proteins, Oncology, original, premium_IRCM, Protein Kinase Inhibitors, STAT3 Transcription Factor, top, Transcription Factor HES-1 |
| Date Added | 2021/02/10 - 12:42:12 |
| Date Modified | 2025/01/10 - 11:14:08 |
| Notes and Attachments | Full Text (Attachment) PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
