Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization
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. Althou...
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| Language: | English |
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Elsevier
2018-02-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396418300215 |
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| author | Yiu To Yeung Shuying Yin Bingbing Lu Suyu Fan Ran Yang Ruihua Bai Chengjuan Zhang Ann M. Bode Kangdong Liu Zigang Dong |
| author_facet | Yiu To Yeung Shuying Yin Bingbing Lu Suyu Fan Ran Yang Ruihua Bai Chengjuan Zhang Ann M. Bode Kangdong Liu Zigang Dong |
| author_sort | Yiu To Yeung |
| collection | DOAJ |
| description | 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. |
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| format | Article |
| id | doaj.art-e995ee623b1f4982ab6d9629f6297b67 |
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| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-14T00:23:17Z |
| publishDate | 2018-02-01 |
| publisher | Elsevier |
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| series | EBioMedicine |
| spelling | doaj.art-e995ee623b1f4982ab6d9629f6297b672022-12-21T23:25:09ZengElsevierEBioMedicine2352-39642018-02-0128C516110.1016/j.ebiom.2018.01.017Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing TetraploidizationYiu To Yeung0Shuying Yin1Bingbing Lu2Suyu Fan3Ran Yang4Ruihua Bai5Chengjuan Zhang6Ann M. Bode7Kangdong Liu8Zigang Dong9The China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, ChinaThe China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, ChinaThe China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, ChinaThe China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, ChinaThe China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, ChinaThe Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, ChinaThe Affiliated Cancer Hospital, Zhengzhou University, Zhengzhou, Henan, ChinaThe Hormel Institute, University of Minnesota, Austin, MN, USAThe China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, ChinaThe China-US (Henan) Hormel Cancer Institute, Zhengzhou, Henan, ChinaThe 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.http://www.sciencedirect.com/science/article/pii/S2352396418300215Non-small cell lung cancer (NSCLC)Gefitinib resistanceTetraploidizationp38 mitogen activating protein kinase (MAPK)Losmapimod |
| spellingShingle | Yiu To Yeung Shuying Yin Bingbing Lu Suyu Fan Ran Yang Ruihua Bai Chengjuan Zhang Ann M. Bode Kangdong Liu Zigang Dong Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization EBioMedicine Non-small cell lung cancer (NSCLC) Gefitinib resistance Tetraploidization p38 mitogen activating protein kinase (MAPK) Losmapimod |
| title | Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization |
| title_full | Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization |
| title_fullStr | Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization |
| title_full_unstemmed | Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization |
| title_short | Losmapimod Overcomes Gefitinib Resistance in Non-small Cell Lung Cancer by Preventing Tetraploidization |
| title_sort | losmapimod overcomes gefitinib resistance in non small cell lung cancer by preventing tetraploidization |
| topic | Non-small cell lung cancer (NSCLC) Gefitinib resistance Tetraploidization p38 mitogen activating protein kinase (MAPK) Losmapimod |
| url | http://www.sciencedirect.com/science/article/pii/S2352396418300215 |
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