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Suppression of Mig-6 overcomes the acquired EGFR-TKI resistance of lung adenocarcinoma.
Kang, Da Hyun; Jung, Sung Soo; Yeo, Min-Kyung; Lee, Da Hye; Yoo, Geon; Cho, Sang Yeon; Oh, In-Jae; Kim, Ju-Ock; Park, Hee Sun; Chung, Chaeuk; Lee, Jeong Eun.
Afiliación
  • Kang DH; Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • Jung SS; Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • Yeo MK; Department of Pathology, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • Lee DH; Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • Yoo G; Korea Institute of Toxicology, 141 Gajeong-ro, Yuseong-gu, Daejeon, 34114, Republic of Korea.
  • Cho SY; Chungnam National University School of Medicine, Daejeon, Republic of Korea.
  • Oh IJ; Department of Internal Medicine, Chonnam National University Medical School, 322 Seoyangro, Hwasun-eup, Hwasun, Jeonnam, 58128, Republic of Korea.
  • Kim JO; Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • Park HS; Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea.
  • Chung C; Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea. universe7903@gmail.com.
  • Lee JE; Division of Pulmonology, Department of Internal Medicine, College of Medicine, Chungnam National University, Daejeon, 35015, Republic of Korea. jelee0210@cnu.ac.kr.
BMC Cancer ; 20(1): 571, 2020 Jun 18.
Article en En | MEDLINE | ID: mdl-32552717
ABSTRACT

BACKGROUND:

The resistance of lung cancer to epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is one of the unconquered frontiers in chemotherapy. Mitogen-inducible gene 6 (Mig-6) is known to inhibit the kinase activity of epidermal growth factor receptor (EGFR). Similarly, numerous studies of mouse models suggested tumor suppressive function of Mig-6 in lung cancer. On the contrary, the results of clinical investigations revealed that lung cancer patients with elevated expression of Mig-6 are associated with a poor prognosis. More recent work showed that unlike wild type (WT) EGFR, mutant EGFR phosphorylates Mig-6 and phosphorylated Mig-6 negatively regulates the degradation of EGFR mutants in lung adenocarcinoma. Here, we tried to untangle the controversies surrounding Mig-6 function as a protagonist or an antagonist of EGFR-TKI resistant lung cancer.

METHODS:

We compared the expression and phosphorylation status of Mig-6 in the EGFR-TKI resistant lung adenocarcinoma (PC9/GR cells) to EGFR-TKI sensitive lung adenocarcinoma (PC9 cells). We investigated the function of Mig-6 by either depletion or overexpression of Mig-6 in those cells and evaluated the efficacy of combining of Mig-6 knock-down and EGFR-TKI treatment in PC9/GR. The correlation between Mig-6 expressions and the prognoses of lung adenocarcinoma was examined by The Cancer Genome Atlas (TCGA) data and clinical samples.

RESULTS:

Our results indicated that the expression of Mig-6 was significantly increased in PC9/GR cells compared to that of PC9 cells. The significant portion of Mig-6 existed as a phosphorylated form in PC9 and PC9/GR cells. Moreover, overexpression of Mig-6 significantly increased the cell proliferation, invasion and epithelial mesenchymal transition (EMT) in PC9 cells. Combination of Mig-6 knock-down and EGFR-TKI treatment significantly overcame the EGFR-TKI resistance of PC9/GR cells. In addition, our analyses of clinical samples confirmed that high Mig-6 expressions positively correlate with a poor prognosis and EGFR-TKI resistance in lung adenocarcinoma.

CONCLUSION:

Our findings reinforce scientific notion of Mig-6 as an oncoprotein in the context of EGFR-TKI resistant lung adenocarcinoma. We propose that targeting Mig-6 may be a promising strategy to overcome the EGFR-TKI resistance in lung cancer.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Proteínas Supresoras de Tumor / Proteínas Adaptadoras Transductoras de Señales / Inhibidores de Proteínas Quinasas / Adenocarcinoma del Pulmón / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Idioma: En Año: 2020 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Resistencia a Antineoplásicos / Proteínas Supresoras de Tumor / Proteínas Adaptadoras Transductoras de Señales / Inhibidores de Proteínas Quinasas / Adenocarcinoma del Pulmón / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Idioma: En Año: 2020 Tipo del documento: Article