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Molecular mechanism of acquired drug resistance in the EGFR-TKI resistant cell line HCC827-TR.

ABSTRACT: BACKGROUND:The first-line standard treatment of non-small cell lung cancer (NSCLC) with EGFR mutation is EGFR-tyrosine kinase inhibitors (TKIs). However, most patients will develop acquired resistance after 9-13?months. This study investigated novel molecular mechanisms of acquired resistance to EGFR-TKIs to identify a potential new treatment for EGFR-TKI resistant NSCLC patients. METHODS:We established an EGFR-TKI resistant cell line (HCC827-TR) by culturing the HCC827-P cell line through continuous erlotinib culture. We used Sanger sequencing, RT-PCR, and western blot to rule out known resistance mechanisms in HCC827-TR cells, including EGFR-T790M and MET, PTEN, or EGFR expression changes. Next-generation sequencing was performed and identified differentially expressed genes between two cell lines and examined the genes with GO and KEGG pathway database analyses. We also examined the molecular alterations in COSMIC and GDSC databases and performed hazard predictions using SIFT, PolyPhen-2, Mutation Taster, and CADD. RESULTS:Our results identified FGF2 as a differentially expressed gene with a G101T point mutation in HCC827-TR cells that showed high mutation frequency and hazard score. HCC827-TR cells showed elevated FGF2 compared to parental cells. It is noteworthy that treatment with the FGFR inhibitor AZD4547 could restore the sensitivity of HCC872-TR cells to erlotinib. CONCLUSIONS:An erlotinib-resistant cell line HCC827-TR was successfully constructed and we identified the EGFR-TKI resistance mechanism involving the FGF2 gene mutation. Targeted inhibition of the FGF2/FGFR signaling pathway may effectively restore the sensitivity of the resistant cells to erlotinib. These results suggest a novel treatment strategy for EGFR-TKI resistant NSCLC patients. KEY POINTS:Significant findings of the study: Identifies a novel molecular mechanism for EGFR-TKI acquired resistance. WHAT THIS STUDY ADDS:A potential novel strategy for the treatment of EGFR-TKI resistant NSCLC patients.

SUBMITTER: Yu T

PROVIDER: S-EPMC7180561 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Molecular mechanism of acquired drug resistance in the EGFR-TKI resistant cell line HCC827-TR.

Yu Tao T Xia Qian Q Gong Ting T Wang Jing J Zhong DianSheng D

Thoracic cancer 20200312 5

<h4>Background</h4>The first-line standard treatment of non-small cell lung cancer (NSCLC) with EGFR mutation is EGFR-tyrosine kinase inhibitors (TKIs). However, most patients will develop acquired resistance after 9-13 months. This study investigated novel molecular mechanisms of acquired resistance to EGFR-TKIs to identify a potential new treatment for EGFR-TKI resistant NSCLC patients.<h4>Methods</h4>We established an EGFR-TKI resistant cell line (HCC827-TR) by culturing the HCC827-P cell lin ...[more]

PMID: 32163227

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Project description: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.

Project description:ObjectivesWe compared mortality between HIV-positive and HIV-negative South African adults with drug-resistant tuberculosis (DR-TB) and high incidence of acquired second-line drug resistance.MethodsWe performed a retrospective review of DR-TB patients with serial second-line TB drug susceptibility tests (2008-2015) who were hospitalized at a specialized TB hospital. We used Kaplan-Meier analysis and Cox models to examine associations with mortality.ResultsOf 245 patients, the median age was 33 years, 54% were male and 40% were HIV-positive, 96% of whom had ever received antiretroviral therapy (ART). At initial drug resistance detection, 99% of patients had resistance to at least rifampicin and isoniazid, and 18% had second-line drug resistance (fluoroquinolones and/or injectable drugs). At later testing, 88% of patients had acquired additional second-line drug resistance. Patient-initiated treatment interruptions (> 2 months) occurred in 47%. Mortality was 79%. Those with HIV had a shorter time to death (p = 0.02; log-rank): median survival time from DR-TB treatment initiation was 2.44 years [95% confidence interval (CI): 2.09-3.15] versus 3.99 years (95% CI: 3.12-4.75) for HIV-negative patients. HIV-positive patients who received ART within 6 months before DR-TB treatment had a higher mortality hazard than HIV-negative patients [adjusted hazard ratio (aHR) ratio = 1.82, 95% CI: 1.21-2.74]. By contrast, HIV-positive patients who did not receive ART within 6 months before DR-TB treatment did not have a significantly higher mortality hazard than HIV-negative patients (aHR = 1.09; 95% CI: 0.72-1.65), although those on ART had lower median CD4 counts than those not on ART (157 vs. 281 cells/μL, respectively; p = 0.02).ConclusionsA very high incidence of acquired second-line drug resistance and high overall mortality were observed, reinforcing the need to reduce the risk of acquired resistance and for more effective treatment.

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Molecular mechanism of acquired drug resistance in the EGFR-TKI resistant cell line HCC827-TR.

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Molecular mechanism of acquired drug resistance in the EGFR-TKI resistant cell line HCC827-TR.

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