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Drug-Induced Resistance and Phenotypic Switch in Triple-Negative Breast Cancer Can Be Controlled via Resolution and Targeting of Individualized Signaling Signatures.
Vasudevan, Swetha; Adejumobi, Ibukun A; Alkhatib, Heba; Roy Chowdhury, Sangita; Stefansky, Shira; Rubinstein, Ariel M; Kravchenko-Balasha, Nataly.
Afiliación
  • Vasudevan S; The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
  • Adejumobi IA; The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
  • Alkhatib H; The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
  • Roy Chowdhury S; The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
  • Stefansky S; The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
  • Rubinstein AM; The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
  • Kravchenko-Balasha N; The Institute of Biomedical and Oral Research, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel.
Cancers (Basel) ; 13(19)2021 Oct 06.
Article en En | MEDLINE | ID: mdl-34638492
Triple-negative breast cancer (TNBC) is an aggressive subgroup of breast cancers which is treated mainly with chemotherapy and radiotherapy. Epidermal growth factor receptor (EGFR) was considered to be frequently expressed in TNBC, and therefore was suggested as a therapeutic target. However, clinical trials of EGFR inhibitors have failed. In this study, we examine the relationship between the patient-specific TNBC network structures and possible mechanisms of resistance to anti-EGFR therapy. Using an information-theoretical analysis of 747 breast tumors from the TCGA dataset, we resolved individualized protein network structures, namely patient-specific signaling signatures (PaSSS) for each tumor. Each PaSSS was characterized by a set of 1-4 altered protein-protein subnetworks. Thirty-one percent of TNBC PaSSSs were found to harbor EGFR as a part of the network and were predicted to benefit from anti-EGFR therapy as long as it is combined with anti-estrogen receptor (ER) therapy. Using a series of single-cell experiments, followed by in vivo support, we show that drug combinations which are not tailored accurately to each PaSSS may generate evolutionary pressure in malignancies leading to an expansion of the previously undetected or untargeted subpopulations, such as ER+ populations. This corresponds to the PaSSS-based predictions suggesting to incorporate anti-ER drugs in certain anti-TNBC treatments. These findings highlight the need to tailor anti-TNBC targeted therapy to each PaSSS to prevent diverse evolutions of TNBC tumors and drug resistance development.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Cancers (Basel) Año: 2021 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Suiza
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Tipo de estudio: Prognostic_studies Idioma: En Revista: Cancers (Basel) Año: 2021 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Suiza