2. Academic Validation
  3. Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma

Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma

  • J Clin Invest. 2020 Feb 3;130(2):612-624. doi: 10.1172/JCI126896.
Emilie Bousquet Mur 1,  Sara Bernardo 1,  Laura Papon 1,  Maicol Mancini 1,  Eric Fabbrizio 1,  Marion Goussard 1,  Irene Ferrer 1 2 3,  Anais Giry 1,  Xavier Quantin 1,  Jean-Louis Pujol 1 4,  Olivier Calvayrac 5,  Herwig P Moll 6,  Yaël Glasson 7,  Nelly Pirot 7,  Andrei Turtoi 8,  Marta Cañamero 9,  Kwok-Kin Wong 10,  Yosef Yarden 11,  Emilio Casanova 6 12,  Jean-Charles Soria 13,  Jacques Colinge 8,  Christian W Siebel 14,  Julien Mazieres 5 15,  Gilles Favre 5,  Luis Paz-Ares 2 4 16,  Antonio Maraver 1
Affiliations

Affiliations

  • 1 Institut de Recherche en Cancérologie de Montpellier (IRCM), Université de Montpellier, Institut Régional du Cancer de Montpellier (ICM), Montpellier, France.
  • 2 Unidad de Investigación Clínica de Cáncer de Pulmón, Instituto de Investigación Hospital 12 de Octubre-CNIO, Madrid, Spain.
  • 3 CIBERONC, Madrid, Spain.
  • 4 Montpellier Academic Hospital, Hôpital Arnaud de Villeneuve, Montpellier, France.
  • 5 INSERM, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France; Institut Claudius Regaud, IUCT-Oncopole, Laboratoire de Biologie Médicale Oncologique, Toulouse, France; University of Toulouse III (Paul Sabatier), Toulouse, France.
  • 6 Department of Physiology, Center of Physiology and Pharmacology and Comprehensive Cancer Center (CCC), Medical University of Vienna, Vienna, Austria.
  • 7 Réseau d'Histologie Expérimentale de Montpellier, BioCampus, UMS3426 CNRS-US009 INSERM-UM, Montpellier, France.
  • 8 IRCM, Université de Montpellier, ICM, Montpellier, France.
  • 9 Roche Pharmaceutical Research and Early Development, Translational Medicine, Roche Innovation Center, Munich, Germany.
  • 10 Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center, New York, New York, USA.
  • 11 Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
  • 12 Ludwig Boltzmann Institute for Cancer Research (LBI-CR), Vienna, Austria.
  • 13 Drug Development Department (DITEP), Gustave Roussy Cancer Campus, Paris-Sud University, Villejuif, France.
  • 14 Department of Discovery Oncology, Genentech, Inc., South San Francisco, California, USA.
  • 15 Thoracic Oncology Department, Larrey Hospital, University Hospital of Toulouse, France; INSERM, Centre de Recherche en Cancérologie de Toulouse, CRCT UMR-1037, Toulouse, France; University of Toulouse III (Paul Sabatier), Toulouse, France.
  • 16 Medical School, Universidad Complutense, Madrid, Spain.
PMID: 31671073 DOI: 10.1172/JCI126896
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.

Keywords

Drug therapy; Lung cancer; Oncology.

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