TY - JOUR
T1 - Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma
AU - Mur, Emilie Bousquet
AU - Bernardo, Sara
AU - Papon, Laura
AU - Mancini, Maicol
AU - Fabbrizio, Eric
AU - Goussard, Marion
AU - Ferrer, Irene
AU - Giry, Anais
AU - Quantin, Xavier
AU - Pujol, Jean-Louis
AU - Calvayrac, Olivier
AU - Moll, Herwig P.
AU - Glasson, Yael
AU - Pirot, Nelly
AU - Turtoi, Andrei
AU - Canamero, Marta
AU - Wong, Kwok-Kin
AU - Yarden, Yosef
AU - Casanova, Emilio
AU - Soria, Jean-Charles
AU - Colinge, Jacques
AU - Siebel, Christian W.
AU - Mazieres, Julien
AU - Favre, Gilles
AU - Paz-Ares, Luis
AU - Maraver, Antonio
N1 - We thank Daniel Herranz, Laurent Le Cam, Daniel Fisher, Hélène Tourriere, and Manuel Serrano for helpful discussion and critical reading of the manuscript. Elisabetta Andermarcher professionally edited the manuscript. We thank Dom Helmlinger for technical help with the RNA-Seq. We thank Simon Cabello-Aguilar for his help uploading the RNA-Seq into the NCBI’s GEO database. We thank the IRCM’s animal facility unit members for their outstanding work. We thank the immunohistochemistry technical service of Cell Signaling Technology for their help and the immunohistochemistry platform at CNIO for their work. EBM was supported by a contract from Fondation de France. SB was supported by a fellowship from the French Ministry of Education and Research. MM is supported by a fellowship from Fondation ARC. Work in AM’s lab is supported by the Fondation ARC (PJA 20131200405), the European Commission (CIG631390), the Institut de Cancer de Montpellier (ICM) Fondation, and the Institut National du Cancer (INCa 9257 and SIRIC Montpellier Cancer Grant INCa Inserm DGOS 12553). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Author contributions - EBM designed and performed most experiments, analyzed data, and wrote the manuscript. SB performed the experiments for RNA-Seq and, together with LP, performed some experiments. MM, MG, and AG performed some in vivo treatments. EF performed ChIP experiments. IF and LPA developed and performed the PDX experiments. XQ, JLP, OC, JCS, JM, and GF performed experiments on clinical samples. MC performed the immunohistochemical analysis of mouse tumors. HPM and EC supervised the experiments with STAT3. YG and NP performed some immunohistochemistry experiments. KKW supervised the experiments on EGFRT790M/L858R mice. YY supervised the work with PC9 resistant cell lines. AT and JC performed the RNA-Seq analysis. CWS supervised the experiments with NRR1 and NRR3 antibodies. AM designed and supervised the study, secured funding, analyzed data, and wrote the manuscript. All authors discussed the results and commented on the manuscript.
PY - 2020/2/3
Y1 - 2020/2/3
N2 - EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFR(T)(790M) m and EGFR(C)(797S). 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(T)(790M) and EGFR(C)(797S) 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(T)(790M) and EGFR(C)(797S) 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.
AB - EGFR-mutated lung adenocarcinoma patients treated with gefitinib and osimertinib show a therapeutic benefit limited by the appearance of secondary mutations, such as EGFR(T)(790M) m and EGFR(C)(797S). 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(T)(790M) and EGFR(C)(797S) 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(T)(790M) and EGFR(C)(797S) 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.
UR - http://www.scopus.com/inward/record.url?scp=85078866464&partnerID=8YFLogxK
U2 - 10.1172/JCI126896
DO - 10.1172/JCI126896
M3 - مقالة
SN - 0021-9738
VL - 130
SP - 612
EP - 624
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 2
ER -