2. Academic Validation
  3. Inhibition of MEK5/ERK5 signaling overcomes acquired resistance to the third generation EGFR inhibitor, osimertinib, via enhancing Bim-dependent apoptosis

Inhibition of MEK5/ERK5 signaling overcomes acquired resistance to the third generation EGFR inhibitor, osimertinib, via enhancing Bim-dependent apoptosis

  • Cancer Lett. 2021 Oct 28;519:141-149. doi: 10.1016/j.canlet.2021.07.007.
Wen Zhao 1,  Danlei Yu 2,  Zhen Chen 3,  Weilong Yao 4,  Jin Yang 5,  Suresh S Ramalingam 3,  Shi-Yong Sun 6
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China; Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
  • 2 Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
  • 3 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
  • 4 Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, Beijing, PR China; Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA.
  • 5 Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China.
  • 6 Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA, USA. Electronic address: ssun@emory.edu.
PMID: 34245854 DOI: 10.1016/j.canlet.2021.07.007
Abstract

The promising therapeutic efficacy of the third generation EGFR inhibitor, osimertinib (AZD9291), for the treatment of patients with EGFR-mutant non-small cell lung Cancer (NSCLC) has been demonstrated in the clinic both as first-line and second line therapy. However, inevitable acquired resistance limits its long-term benefit to patients and is thus a significant clinical challenge. The current study focuses on studying the potential role of targeting MEK5-ERK5 signaling in overcoming acquired resistance to osimertinib. Osimertinib and other third generation EGFR inhibitors exerted a rapid and sustained suppressive effect on ERK5 phosphorylation primarily in EGFR-mutant NSCLC cell lines and lost this activity in some osimertinib-resistant cell lines. Osimertinib combined with either ERK5 or MEK5 inhibitors synergistically decreased the survival of osimertinib-resistant cell lines with enhanced induction of Apoptosis primarily via augmenting Bim expression. Moreover, the combination effectively inhibited the growth of osimertinib-resistant xenografts in vivo. Together, these findings suggest the potential role of MEK5-ERK5 signaling in modulating development of acquired resistance to osimertinib and value of targeting this signaling as a potential strategy in overcoming acquired resistance to osimertinib and possibly other third generation EGFR inhibitors.

Keywords

Acquired resistance; Apoptosis; EGFR inhibitors; Lung cancer; MEK5/ERK5.

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