Patient-specific signaling signatures predict optimal therapeutic combinations for triple negative breast cancer

Heba Alkhatib, Jason Conage-Pough, Sangita Roy Chowdhury, Denen Shian, Deema Zaid, Ariel M. Rubinstein, Amir Sonnenblick, Tamar Peretz-Yablonsky, Avital Granit, Einat Carmon, Ishwar N. Kohale, Judy C. Boughey, Matthew P. Goetz, Liewei Wang, Forest M. White*, Nataly Kravchenko-Balasha*

*Corresponding author for this work

Research output: Contribution to journalLetterpeer-review

Abstract

Triple negative breast cancer (TNBC) is a heterogeneous group of tumors which lack estrogen receptor, progesterone receptor, and HER2 expression. Targeted therapies have limited success in treating TNBC, thus a strategy enabling effective targeted combinations is an unmet need. To tackle these challenges and discover individualized targeted combination therapies for TNBC, we integrated phosphoproteomic analysis of altered signaling networks with patient-specific signaling signature (PaSSS) analysis using an information-theoretic, thermodynamic-based approach. Using this method on a large number of TNBC patient-derived tumors (PDX), we were able to thoroughly characterize each PDX by computing a patient-specific set of unbalanced signaling processes and assigning a personalized therapy based on them. We discovered that each tumor has an average of two separate processes, and that, consistent with prior research, EGFR is a major core target in at least one of them in half of the tumors analyzed. However, anti-EGFR monotherapies were predicted to be ineffective, thus we developed personalized combination treatments based on PaSSS. These were predicted to induce anti-EGFR responses or to be used to develop an alternative therapy if EGFR was not present. In-vivo experimental validation of the predicted therapy showed that PaSSS predictions were more accurate than other therapies. Thus, we suggest that a detailed identification of molecular imbalances is necessary to tailor therapy for each TNBC. In summary, we propose a new strategy to design personalized therapy for TNBC using pY proteomics and PaSSS analysis. This method can be applied to different cancer types to improve response to the biomarker-based treatment.

Original languageAmerican English
Article number17
JournalMolecular Cancer
Volume23
Issue number1
DOIs
StatePublished - 16 Jan 2024

Bibliographical note

Publisher Copyright:
© 2024, The Author(s).

Keywords

  • EGFR
  • Information theory
  • Patient-specific signaling signatures
  • Personalized combined treatment
  • Phosphotyrosine proteomics
  • Targeted therapy
  • Triple-negative breast cancer

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