Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer
Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free surviva...
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| Veröffentlicht in: | Scientific reports 2019-12, Vol.9 (1), p.18842-12, Article 18842 |
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| description | Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin dependent kinase inhibitor compared to crizotinib alone. The results support the hypothesis that combining MEK inhibitors with ALK inhibitor can overcome ALK inhibitor resistance, and identifies Bim, PARP and CDK1 as druggable targets for possible triple drug therapy. |
| doi_str_mv | 10.1038/s41598-019-55376-4 |
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Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin dependent kinase inhibitor compared to crizotinib alone. 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J.</creatorcontrib><creatorcontrib>Ashton, J. C.</creatorcontrib><title>Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin dependent kinase inhibitor compared to crizotinib alone. 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J.</au><au>Ashton, J. C.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2019-12-11</date><risdate>2019</risdate><volume>9</volume><issue>1</issue><spage>18842</spage><epage>12</epage><pages>18842-12</pages><artnum>18842</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><abstract>Anaplastic lymphoma kinase (ALK) rearrangement, a key oncogenic driver in a small subset of non-small cell lung cancers, confers sensitivity to ALK tyrosine kinase inhibitors (TKIs). Crizotinib, a first generation ALK-TKI, has superiority to standard chemotherapy with longer progression-free survival and higher objective response rate. However, clinical benefit is limited by development of resistance, typically within a year of therapy. In this study the combined effect of crizotinib and the MEK inhibitor selumetinib was investigated in both crizotinib naïve (H3122) and crizotinib resistant (CR-H3122) ALK-positive lung cancer cells. Results showed that combination treatment potently inhibited the growth of both H3122 and CR-H3122 cells, resulting from increased apoptosis and decreased cell proliferation as a consequence of suppressed downstream RAS/MAPK signalling. The drug combination also elicited a greater than 3-fold increase in Bim, a mediator of apoptosis, and p27, a cyclin dependent kinase inhibitor compared to crizotinib alone. The results support the hypothesis that combining MEK inhibitors with ALK inhibitor can overcome ALK inhibitor resistance, and identifies Bim, PARP and CDK1 as druggable targets for possible triple drug therapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31827192</pmid><doi>10.1038/s41598-019-55376-4</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13/1 13/31 13/51 13/95 14 38 38/1 631/67/1059 631/67/1612/1350 64 692/308/153 82 82/1 Anaplastic Lymphoma Kinase - antagonists & inhibitors Anaplastic Lymphoma Kinase - metabolism Antineoplastic Combined Chemotherapy Protocols - pharmacology Antineoplastic Combined Chemotherapy Protocols - therapeutic use Apoptosis Benzimidazoles - pharmacology Benzimidazoles - therapeutic use Carcinoma, Non-Small-Cell Lung - drug therapy Carcinoma, Non-Small-Cell Lung - enzymology Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - physiopathology Cell Cycle Cell growth Cell Line, Tumor Cell Proliferation Crizotinib - pharmacology Crizotinib - therapeutic use Drug Resistance, Neoplasm Drug therapy Enzyme inhibitors Humanities and Social Sciences Humans Kinases Lung cancer Lung Neoplasms - drug therapy Lung Neoplasms - enzymology Lung Neoplasms - metabolism Lung Neoplasms - physiopathology Lymphoma MAP Kinase Kinase Kinases - antagonists & inhibitors MAP Kinase Kinase Kinases - metabolism multidisciplinary Non-small cell lung carcinoma Protein Kinase Inhibitors - pharmacology Protein Kinase Inhibitors - therapeutic use Science Science (multidisciplinary) Signal Transduction Small cell lung carcinoma |
| title | Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer |
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