Open Access

PDGFD induces ibrutinib resistance of diffuse large B‑cell lymphoma through activation of EGFR

  • Authors:
    • Jia Jin
    • Leiping Wang
    • Zhonghua Tao
    • Jian Zhang
    • Fangfang Lv
    • Junning Cao
    • Xichun Hu
  • View Affiliations

  • Published online on: March 12, 2020     https://doi.org/10.3892/mmr.2020.11022
  • Pages: 2209-2219
  • Copyright: © Jin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Ibrutinib, an FDA approved, orally administered BTK inhibitor, has demonstrated high response rates to diffuse large B‑cell lymphoma (DLBCL), however, complete responses are infrequent and acquired resistance to BTK inhibition can emerge. The present study investigated the role of the platelet‑derived growth factor D (PDGFD) gene and the ibrutinib resistance of DLBCL in relation to epidermal growth factor receptor (EGFR). Bioinformatics was used to screen and analyze differentially expressed genes (DEGs) in complete response (CR), partial response (PR) and stable disease (SD) in DLBCL treatment with ibrutinib, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to analyze enriched the signaling pathways increasing DEGs. The Search Tool for Interactions of Chemicals database was used to analyze the target genes of ibrutinib. An interaction network of DEGs, disease‑related genes and ibrutinib was constructed. The expression of PDGFD in tissues that were resistant or susceptible to DLBCL/ibrutinib was detected via immunohistochemistry (IHC), and the expression of PDGFD in DLBCL/ibrutinib‑resistant strains and their parental counterparts were examined via reverse transcription‑quantitative PCR and western blot analyses. Subsequently, a drug‑resistant cell model of DLBCL/ibrutinib in which PDGFD was silenced was constructed. The apoptosis of the DLBCL/ibrutinib‑resistant strains was examined using MTT and flow cytometry assays. EGFR gene expression was then assessed. At the same time, a PDGFD‑interfering plasmid and an EGFR overexpression plasmid were transfected into the DLBCL drug‑resistant cells (TMD8‑ibrutinib, HBL1‑ibrutinib) separately or together. MTT was used to measure cell proliferation and changes in the IC50 of ibrutinib. A total of 86 DEGs that increased in the CR, PR and SD tissues were screened, and then evaluated with GO and KEGG. The interaction network diagram showed that there was a regulatory relationship between PDGFD and disease‑related genes, and that PDGFD could indirectly target the ibrutinib target gene EGFR, indicating that PDGFD could regulate DLBCL via EGFR. IHC results showed high expression of PDGFD in diffuse large B‑cell lymphoma tissues with ibrutinib tolerance. PDGFD expression in ibrutinib‑resistant DLBCL cells was higher compared with in parental cells. Following interference with PDGFD expression in ibrutinib‑resistant DLBCL cells, the IC50 value of ibrutinib decreased, the rate of apoptosis increased and EGFR expression decreased. In brief, EGFR overexpression can reverse the resistance of DLBCL to ibrutinib via PDGFD interference, and PDGFD induces the resistance of DLBCL to ibrutinib via EGFR.

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May 2020
Volume 21 Issue 5

Print ISSN: 1791-2997
Online ISSN:1791-3004

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APA
Jin, J., Wang, L., Tao, Z., Zhang, J., Lv, F., Cao, J., & Hu, X. (2020). PDGFD induces ibrutinib resistance of diffuse large B‑cell lymphoma through activation of EGFR. Molecular Medicine Reports, 21, 2209-2219. https://doi.org/10.3892/mmr.2020.11022
MLA
Jin, J., Wang, L., Tao, Z., Zhang, J., Lv, F., Cao, J., Hu, X."PDGFD induces ibrutinib resistance of diffuse large B‑cell lymphoma through activation of EGFR". Molecular Medicine Reports 21.5 (2020): 2209-2219.
Chicago
Jin, J., Wang, L., Tao, Z., Zhang, J., Lv, F., Cao, J., Hu, X."PDGFD induces ibrutinib resistance of diffuse large B‑cell lymphoma through activation of EGFR". Molecular Medicine Reports 21, no. 5 (2020): 2209-2219. https://doi.org/10.3892/mmr.2020.11022