Elsevier

EBioMedicine

Volume 28, February 2018, Pages 51-61
EBioMedicine

Research Paper
Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization

https://doi.org/10.1016/j.ebiom.2018.01.017Get rights and content
Under a Creative Commons license
open access

Highlights

  • Gefitinib induces tetraploidy formation in gefitinib-resistant NSCLC cells

  • YAP-MKK3/6-p38 MAPK signaling is essential for tetraploidization

  • Losmapimod, a p38 MAPK inhibitor, overcomes gefitinib-resistance both in vitro and PDX xenograft mode

Gefitinib is a targeted drug therapy in non-small cell lung cancer (NSCLC) which shows dramatic clinical efficacy. However, most of these patients eventually develop drug resistance. Although researchers have identified different mechanisms contributing to the drug resistance, developing a single therapy to overcome the drug resistance remains difficult. In this study, we find that tetraploidization of cancer cells through YAP-MKK3/6-p38 MAPK signaling could be one of the common mechanisms in developing the drug resistance. By using losmapimod, we could eliminate tetraploidization and overcome gefitinib resistance in an animal model suggesting that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC.

Abstract

The epidermal growth factor receptor (EGFR) is known to play a critical role in non-small cell lung cancer (NSCLC). Constitutively active EGFR mutations, including in-frame deletion in exon 19 and L858R point mutation in exon 21, contribute about 90% of all EGFR-activating mutations in NSCLC. Although oral EGFR-tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, show dramatic clinical efficacy with significantly prolonged progression-free survival in patients harboring these EGFR-activating mutations, most of these patients will eventually develop acquired resistance. Researchers have recently named genomic instability as one of the hallmarks of cancer. Genomic instability usually involves a transient phase of polyploidization, in particular tetraploidization. Tetraploid cells can undergo asymmetric cell division or chromosome loss, leading to tumor heterogeneity and multidrug resistance. Therefore, identification of signaling pathways involved in tetraploidization is crucial in overcoming drug resistance. In our present study, we found that gefitinib could activate YAP-MKK3/6-p38 MAPK-STAT3 signaling and induce tetraploidization in gefitinib-resistance cells. Using p38 MAPK inhibitors, SB203580 and losmapimod, we could eliminate gefitinib-induced tetraploidization and overcome gefitinib-resistance. In addition, shRNA approach to knockdown p38α MAPK could prevent tetraploidy formation and showed significant inhibition of cancer cell growth. Finally, in an in vivo study, losmapimod could successfully overcome gefitinib resistance using an in-house established patient-derived xenograft (PDX) mouse model. Overall, these findings suggest that losmapimod could be a potential clinical agent to overcome gefitinib resistance in NSCLC.

Keywords

Non-small cell lung cancer (NSCLC)
Gefitinib resistance
Tetraploidization
p38 mitogen activating protein kinase (MAPK)
Losmapimod

Cited by (0)