Notch inhibition overcomes resistance to tyrosine kinase inhibitors in EGFR-driven lung adenocarcinoma
Emilie Bousquet Mur, … , Luis Paz-Ares, Antonio Maraver
Emilie Bousquet Mur, … , Luis Paz-Ares, Antonio Maraver
Published October 31, 2019
Citation Information: J Clin Invest. 2020;130(2):612-624. https://doi.org/10.1172/JCI126896.
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Research Article Oncology

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

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.

Authors

Emilie Bousquet Mur, Sara Bernardo, Laura Papon, Maicol Mancini, Eric Fabbrizio, Marion Goussard, Irene Ferrer, Anais Giry, Xavier Quantin, Jean-Louis Pujol, Olivier Calvayrac, Herwig P. Moll, Yaël Glasson, Nelly Pirot, Andrei Turtoi, Marta Cañamero, Kwok-Kin Wong, Yosef Yarden, Emilio Casanova, Jean-Charles Soria, Jacques Colinge, Christian W. Siebel, Julien Mazieres, Gilles Favre, Luis Paz-Ares, Antonio Maraver

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Figure 7

High HES1 protein levels correlate with poor progression-free survival and relapse in EGFR-mutated lung adenocarcinoma patients under TKI treatment.

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High HES1 protein levels correlate with poor progression-free survival a...
(A) PC9GR cells were injected subcutaneously into nude mice. The mice were then treated with vehicle (methocel, n = 6), DBZ (n = 6), nirogacestat (n = 6), gefitinib (n = 6), or the combination of DBZ and gefitinib (n = 7), or the combination of nirogacestat and gefitinib (n = 7). The y axis shows the tumor growth fold increase versus day 0 and the x axis the days after treatment. Values correspond to the average ± SEM. Statistical significance was determined by 2-way ANOVA followed by Tukey’s post hoc test. ****P ≤ 0.0001. The differences between DBZ and the combination DBZ/gefitinib or nirogacestat/gefitinib were also significant (P ≤ 0.0001 and P ≤ 0.001, respectively), as was the difference between nirogacestat and the combination DBZ/gefitinib or nirogacestat/gefitinib (P ≤ 0.0001 for both). The difference between gefitinib alone and the combination DBZ plus gefitinib was also significant (P ≤ 0.01). (B) PC9GR cells were injected subcutaneously in nude mice. The mice were then treated with vehicle (methocel, n = 5), nirogacestat (n = 6), gefitinib (n = 6), or the combination of DBZ and gefitinib (n = 7). The y axis shows the percentage of surviving animals and the x axis the days after treatment. Statistical significance was determined by the Gehan-Breslow-Wilcoxon test. Vehicle vs. gefitinib (P = 0.3), vehicle vs. nirogacestat (P = 0.93), vehicle vs. the combination (P = 0.02), gefitinib vs. the combination (P = 0.05), and nirogacestat vs. the combination (P = 0.02). (C) Progression-free survival of EGFR TKI–treated patients with EGFR-mutated lung adenocarcinoma (n = 75) according to HES1 expression assessed by immunohistochemical staining (low HES1 = 0–2.50 HES1 score; high HES1 = 2.51–5.00 HES1 score). Statistical significance was determined by the Gehan-Breslow-Wilcoxon test. (D) Representation of the change in HES1 immunohistochemical staining intensity score in patient samples before treatment (dots) and after relapse (arrowheads). Statistical significance was determined by paired 2-tailed Student’s t test.