Dataset Information

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses.

ABSTRACT:

Purpose

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) show efficacy in treating patients with lung adenocarcinoma with EGFR-activating mutations. However, a significant subset of targeted patients fail to respond. Unlike acquired resistance (AR), intrinsic resistance (IR) remains poorly understood. We investigated whether epigenomic factors contribute to patient-to-patient heterogeneity in the EGFR-TKI response and aimed to characterize the IR subpopulation that obtains no benefit from EGFR-TKIs.

Patients and methods

We conducted genome-wide DNA methylation profiling of 79 tumors sampled from patients with advanced lung adenocarcinoma before they received EGFR-TKI treatment and analyzed the patient responses. Pyrosequencing was performed in a validation cohort of 163 patients with EGFR-activating mutations.

Results

A DNA methylation landscape of 216 CpG sites with differential methylation was established to elucidate the association of DNA methylation with the characteristics and EGFR-TKI response status of the patients. Functional analysis of 37 transcription-repressive sites identified the enrichment of transcription factors, notably homeobox (HOX) genes. DNA methylation of HOXB9 (cg13643585) in the enhancer region yielded 88% sensitivity for predicting drug response (odds ratio [OR], 6.64; 95% CI, 1.98 to 25.23; P = .0009). Pyrosequencing validated that HOXB9 gained methylation in patients with a poor EGFR-TKI response (OR, 3.06; 95% CI, 1.13 to 8.19; P = .019).

Conclusion

Our data suggest that homeobox DNA methylation could be a novel tumor cellular state that can aid the precise categorization of tumor heterogeneity in the study of IR to EGFR-TKIs. We identified, for the first time, an epigenomic factor that can potentially complement DNA mutation status in discriminating patients with lung adenocarcinoma who are less likely to benefit from EGFR-TKI treatment, thereby leading to improved patient management in precision medicine.

SUBMITTER: Su SF

PROVIDER: S-EPMC8140798 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Publications

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses.

Su Sheng-Fang SF Liu Chia-Hsin CH Cheng Chiou-Ling CL Ho Chao-Chi CC Yang Tsung-Ying TY Chen Kun-Chieh KC Hsu Kuo-Hsuan KH Tseng Jeng-Sen JS Chen Huei-Wen HW Chang Gee-Chen GC Yu Sung-Liang SL Li Ker-Chau KC

JCO precision oncology 20210219

<h4>Purpose</h4>Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) show efficacy in treating patients with lung adenocarcinoma with <i>EGFR</i>-activating mutations. However, a significant subset of targeted patients fail to respond. Unlike acquired resistance (AR), intrinsic resistance (IR) remains poorly understood. We investigated whether epigenomic factors contribute to patient-to-patient heterogeneity in the EGFR-TKI response and aimed to characterize the IR subpopula ...[more]

PMID: 34036228

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Project description:BackgroundKeeping on original epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment is the standard treatment for gradual progression EGFR-positive metastatic non-small cell lung cancer (NSCLC). Angiogenic pathway can lead to EGFR-TKI resistance, but the effectiveness of combination strategies in this group is still controversial. This study aimed to assess the efficacy and safety of the original EGFR-TKI combined with bevacizumab in advanced and metastatic lung adenocarcinoma patients harboring EGFR-mutation who experience gradual progression in a real-world setting.MethodsFrom June 2019 to December 2021, a total of 35 metastatic EGFR positive NSCLC patients experienced gradual progression after EGFR-TKI treatments and received original TKI combined with bevacizumab were identified at Chongqing University Cancer Hospital, China. All patients were confirmed EGFR positive by rebiopsy before treatment. Patients were treated with EGFR-TKI and bevacizumab (15 mg/kg Q3W) after gradual progression until rapid progression or intolerable toxicity. The overall survival (OS), progression-free survival 1 (PFS1, period from the beginning of EGFR-TKI treatment to the rapid progression of the disease), PFS2 (period from the beginning of EGFR-TKI combined with bevacizumab treatment to the rapid progression of the disease), disease control rate (DCR), and adverse events of the combined treatment were collected and analyzed.ResultsA total of 33 patients could participate the efficacy evaluation. Median PFS1 and PFS2 were 20.5 and 8 months, respectively; DCR was 93.94%; median OS was immature. Multivariate Cox proportional hazards model showed that smoking status [hazard ratio (HR) =3.692, 95% confidence interval (CI): 1.450-9.404, P=0.006], combined EGFR T790M mutation or rare mutation (HR =2.480, 95% CI: 1.073-5.729, P=0.034), and malignant pleural effusion (HR =3.707, 95% CI: 1.460-9.414, P=0.006) were independent risk factors for PFS2. The most common treatment-related adverse events greater than grade 3 included hypertension (23.7%), proteinuria (8.3%), and increased alanine aminotransferase (ALT; 4.1%) and aspartate aminotransferase (AST; 2.9%).ConclusionsContinuous original TKI combined with bevacizumab showed partly favorable efficacy and safety and may represent a therapeutic option for metastatic EGFR-mutation NSCLC patients experiencing gradual progression after EGFR-TKI treatment.

Project description:BackgroundThe 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.MethodsWe 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.ResultsOur 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.ConclusionOur 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.

Dataset Information

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses.

Purpose

Patients and methods

Results

Conclusion

Publications

Genome-Wide Epigenetic Landscape of Lung Adenocarcinoma Links HOXB9 DNA Methylation to Intrinsic EGFR-TKI Resistance and Heterogeneous Responses.

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