Drug‐induced resistance and phenotypic switch in triple‐negative breast cancer can be controlled via resolution and targeting of individualized signaling signatures

Swetha Vasudevan, Ibukun A. Adejumobi, Heba Alkhatib, Sangita Roy Chowdhury, Shira Stefansky, Ariel M. Rubinstein, Nataly Kravchenko‐balasha

Research output: Contribution to journalArticlepeer-review

9 Scopus citations


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 rela-tionship 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 unde-tected 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 find-ings highlight the need to tailor anti‐TNBC targeted therapy to each PaSSS to prevent diverse evo-lutions of TNBC tumors and drug resistance development.

Original languageAmerican English
Article number5009
Issue number19
StatePublished - 1 Oct 2021

Bibliographical note

Funding Information:
Funding: The funding sources for this work were from Israel Science Foundation (ISF, 1961/19) and NIH/National Cancer Institute (U01 CA238720).

Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.


  • Anti‐EGFR therapy
  • Drug resistance
  • Patient‐specific altered signaling signatures
  • Precision medicine
  • Targeted therapy
  • Triple negative breast cancer
  • patient-specific altered signaling signatures
  • targeted therapy
  • precision medicine
  • anti-EGFR therapy
  • triple negative breast cancer
  • drug resistance


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