EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Selenz, Carolin; Compes, Anik; Nill, Marieke; Borchmann, Sven; Odenthal, Margarete; Florin, Alexandra; Brägelmann, Johannes; Buettner, Reinhard; Meder, Lydia; Ullrich, Roland T.

doi:10.3390/cancers14163943

Cited by 15 publications

(9 citation statements)

References 46 publications

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“…For instance, Al-Wahaibi and colleagues synthesized indole-2-carboxamides and prove its antiproliferative and apoptotic activities through EGFR/CDK2 inhibition 49 . The inhibition of EGFR was also associated with tumor microenvironment modulation in non-small cell lung cancer 50 . The inhibition of ESR1 also represses tumor growth in diverse cancer, including breast cancer 51,52 .…”

Section: Discussionmentioning

confidence: 97%

Integrating network pharmacology and pharmacological evaluation to investigate the anticancer effects of Duranta erecta Linn. Verbenaceae in breast cancer

Agbana¹,

Abu²,

Akinleye³

et al. 2023

Preprint

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Objective Breast cancer is the most prevalent type of cancer among women in sub-Saharan Africa. Efforts are being made to tackle the disease. However, numerous challenges are still reported. Duranta erecta showed medicinal relevance in different ailments but its molecular mechanism of action in breast cancer is not unraveled. The objective of this study is to evaluate the anticancer effect of Duranta erecta on breast cancer cells and determine the molecular mechanism of action in silico. Materials and Methods The Phytochemical Interaction Database, published literature, and the Swiss TargetPrediction database, respectively, were used to identify the active ingredients and targets of Duranta erecta. GEO datasets and TCGA databases were searched for breast cancer-related targets. A protein-protein interaction (PPI) network was constructed to screen the primary targets. For GO and KEGG pathway enrichment analyses, ShinyGO was used. By using molecular docking, interactions between potential targets and active substances were evaluated. MTT assay was conducted to evaluate the cytotoxicity effect of Duranta erecta. Results Duranta erecta demonstrated a cytotoxic effect on breast cancer cells. The IC50 values are 9.99 µg/mL and 15.07 µg/mL for the fruit extract and the leaves extract respectively. A total of 102 common targets and 77 active plant compounds were discovered, of which 37 are potential drug candidates. There were 10 hub targets identified by the PPI network. The hub targets are linked to pathways in cell proliferation and cancer. The best overall binding affinity was demonstrated by repenin A in binding with AURKA, CDK1, and EGFR. Conclusion This study was able to accurately predict the active ingredients and potential targets used in Duranta erecta's treatment of breast cancer. This study offers a fresh approach to future deeper studies on the molecular mechanisms of the plant and its compounds in breast cancer.

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Section: Discussionmentioning

confidence: 97%

Integrating network pharmacology and pharmacological evaluation to investigate the anticancer effects of Duranta erecta Linn. Verbenaceae in breast cancer

Agbana¹,

Abu²,

Akinleye³

et al. 2023

Preprint

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“…EGFR mutations induce an un-inflamed TME with less T cell infiltration and increased numbers of Tregs, which results in a more suppressive immune environment (53). EGFR inhibition through TKI treatment is known to enhance MHC class I and II antigen presentation, induce more robust infiltration by immune cells and increases local proliferation of T cells in tumors, which leads to increased activation of immune cells and T-cell mediated tumor killing (54,55). Thus, TKI treatment before (or at the same time) with E mut VAX may potentially offer a better clinical benefit than treatment with TKI after E mut VAX.…”

Section: Discussionmentioning

confidence: 99%

Precision immunointerception of EGFR-driven tumorigenesis for lung cancer prevention

et al. 2023

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Epidermal growth factor receptor (EGFR) mutations occur in about 50% of lung adenocarcinomas in Asia and about 15% in the US. EGFR mutation-specific inhibitors have been developed and made significant contributions to controlling EGFR mutated non-small cell lung cancer. However, resistance frequently develops within 1 to 2 years due to acquired mutations. No effective approaches that target mutant EGFR have been developed to treat relapse following tyrosine kinase inhibitor (TKI) treatment. Vaccination against mutant EGFR is one area of active exploration. In this study, we identified immunogenic epitopes for the common EGFR mutations in humans and formulated a multi-peptide vaccine (Emut Vax) targeting the EGFR L858R, T790M, and Del19 mutations. The efficacy of the Emut Vax was evaluated in both syngeneic and genetic engineered EGFR mutation-driven murine lung tumor models with prophylactic settings, where the vaccinations were given before the onset of the tumor induction. The multi-peptide Emut Vax effectively prevented the onset of EGFR mutation-driven lung tumorigenesis in both syngeneic and genetically engineered mouse models (GEMMs). Flow cytometry and single-cell RNA sequencing were conducted to investigate the impact of Emut Vax on immune modulation. Emut Vax significantly enhanced Th1 responses in the tumor microenvironment and decreased suppressive Tregs to enhance anti-tumor efficacy. Our results show that multi-peptide Emut Vax is effective in preventing common EGFR mutation-driven lung tumorigenesis, and the vaccine elicits broad immune responses that are not limited to anti-tumor Th1 response.

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“…Furthermore, panitumumab reduced the gene expression of immunosuppressive cytokines, including TGFB1, TGFB2, TGFB3, CCL2, and IL1B [ 38 ]. EGFR targeted therapy has been shown to modulate the TME in lung cancer [ 39 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

Copy Number Variation in Inflammatory Breast Cancer

Hazra

O'Hara

Polyák

et al. 2023

Cells

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Identification of a unique genomic biomarker in de novo inflammatory breast cancer (IBC) may provide an insight into the biology of this aggressive disease. The goal of our study was to elucidate biomarkers associated with IBC. We examined breast biopsies collected from Dana–Farber Cancer Institute patients with IBC prior to initiating preoperative systemic treatment (30 samples were examined, of which 14 were eligible). Patients without available biopsies (n = 1), with insufficient tumor epithelial cells (n = 10), or insufficient DNA yield (n = 5) were excluded from the analysis. Molecular subtype and tumor grade were abstracted from a medical records’ review. Ten IBC tumors were estrogen-receptor-positive (ER+) and human epidermal growth factor receptor 2 (HER2)-negative (n = 10 out of 14). Sufficient RNA and DNA were simultaneously extracted from 14 biopsy specimens using the Qiagen AllPrep Kit. RNA was amplified using the Sensation kit and profiled using the Affymetrix Human Transcriptome Array 2.0. DNA was profiled for genome-wide copy number variation (CNV) using the Affymetrix OncoScan Array and analyzed using the Nexus Chromosome Analysis Suite. Among the 14 eligible samples, we first confirmed biological concordance and quality control metrics using replicates and gene expression data. Second, we examined CNVs and gene expression change by IBC subtype. We identified significant CNVs in IBC patients after adjusting for multiple comparisons. Next, to assess whether the CNVs were unique to IBC, we compared the IBC CNV data to fresh-frozen non-IBC CNV data from The Cancer Genome Atlas (n = 388). On chromosome 7p11.2, we identified significant CN gain located at position 58,019,983-58,025,423 in 8 ER+ IBC samples compared to 338 non-IBC ER+ samples (region length: 5440 bp gain and 69,039 bp, False Discovery Rate (FDR) p-value = 3.12 × 10−10) and at position 57,950,944–58,025,423 in 3 TN-IBC samples compared to 50 non-IBC TN samples (74,479 base pair, gain, FDR p-value = 4.27 × 10−5; near the EGFR gene). We also observed significant CN loss on chromosome 21, located at position 9,648,315–9,764,385 (p-value = 4.27 × 10−5). Secondarily, differential gene expression in IBC patients with 7p11.2 CN gain compared to SUM149 were explored after FDR correction for multiple testing (p-value = 0.0016), but the results should be interpreted with caution due to the small sample size. Finally, the data presented are hypothesis-generating. Validation of CNVs that contribute to the unique presentation and biological features associated with IBC in larger datasets may lead to the optimization of treatment strategies.

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EGFR Inhibition Strongly Modulates the Tumour Immune Microenvironment in EGFR-Driven Non-Small-Cell Lung Cancer

Cited by 15 publications

References 46 publications

Integrating network pharmacology and pharmacological evaluation to investigate the anticancer effects of Duranta erecta Linn. Verbenaceae in breast cancer

Integrating network pharmacology and pharmacological evaluation to investigate the anticancer effects of Duranta erecta Linn. Verbenaceae in breast cancer

Precision immunointerception of EGFR-driven tumorigenesis for lung cancer prevention

Copy Number Variation in Inflammatory Breast Cancer

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