1. Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma
- Author
-
Anais Giry, Emilio Casanova, Gilles Favre, Olivier Calvayrac, Jean-Charles Soria, Irene Ferrer, Laura Papon, Yaël Glasson, Julien Mazieres, Nelly Pirot, Luis Paz-Ares, Antonio Maraver, Andrei Turtoi, Kwok-Kin Wong, Jean-Louis Pujol, Eric Fabbrizio, Sara Bernardo, Yosef Yarden, Marion Goussard, Herwig P. Moll, Jacques Colinge, Marta Cañamero, Emilie Bousquet Mur, Christian W. Siebel, Xavier Quantin, Maicol Mancini, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
0301 basic medicine ,STAT3 Transcription Factor ,Lung Neoplasms ,medicine.medical_treatment ,[SDV]Life Sciences [q-bio] ,Mutation, Missense ,Adenocarcinoma of Lung ,Mice, Transgenic ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Gefitinib ,medicine ,Animals ,Osimertinib ,Lung cancer ,STAT3 ,Protein Kinase Inhibitors ,ComputingMilieux_MISCELLANEOUS ,Chemotherapy ,Acrylamides ,Aniline Compounds ,biology ,business.industry ,General Medicine ,medicine.disease ,3. Good health ,respiratory tract diseases ,Neoplasm Proteins ,ErbB Receptors ,030104 developmental biology ,Amino Acid Substitution ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Adenocarcinoma ,Phosphorylation ,Transcription Factor HES-1 ,business ,Tyrosine kinase ,medicine.drug ,Research Article - Abstract
EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFR(T790M) and EGFR(C797S). 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 EGFR(T790M) and EGFR(C797S) 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 EGFR(T790M) and EGFR(C797S) 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.
- Published
- 2019
- Full Text
- View/download PDF