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Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC

Author

Listed:
  • Sukanya Panja

    (Rutgers School of Health Professions)

  • Mihai Ioan Truica

    (Northwestern University Feinberg School of Medicine)

  • Christina Y. Yu

    (Rutgers School of Health Professions)

  • Vamshi Saggurthi

    (Rutgers School of Health Professions)

  • Michael W. Craige

    (Rutgers School of Health Professions)

  • Katie Whitehead

    (Rutgers School of Health Professions)

  • Mayra V. Tuiche

    (Rutgers School of Health Professions
    Rutgers School of Graduate Studies)

  • Aymen Al-Saadi

    (Rutgers School of Engineering)

  • Riddhi Vyas

    (Rutgers School of Health Professions)

  • Shridar Ganesan

    (Rutgers Cancer Institute of New Jersey)

  • Suril Gohel

    (Rutgers School of Health Professions)

  • Frederick Coffman

    (Rutgers School of Health Professions)

  • James S. Parrott

    (Rutgers School of Health Professions)

  • Songhua Quan

    (Northwestern University Feinberg School of Medicine)

  • Shantenu Jha

    (Rutgers School of Engineering)

  • Isaac Kim

    (Rutgers Cancer Institute of New Jersey
    Yale School of Medicine)

  • Edward Schaeffer

    (Northwestern University Feinberg School of Medicine)

  • Vishal Kothari

    (Northwestern University Feinberg School of Medicine)

  • Sarki A. Abdulkadir

    (Northwestern University Feinberg School of Medicine
    Robert H. Lurie Comprehensive Cancer Center)

  • Antonina Mitrofanova

    (Rutgers School of Health Professions
    Rutgers Cancer Institute of New Jersey)

Abstract

Heterogeneous response to Enzalutamide, a second-generation androgen receptor signaling inhibitor, is a central problem in castration-resistant prostate cancer (CRPC) management. Genome-wide systems investigation of mechanisms that govern Enzalutamide resistance promise to elucidate markers of heterogeneous treatment response and salvage therapies for CRPC patients. Focusing on the de novo role of MYC as a marker of Enzalutamide resistance, here we reconstruct a CRPC-specific mechanism-centric regulatory network, connecting molecular pathways with their upstream transcriptional regulatory programs. Mining this network with signatures of Enzalutamide response identifies NME2 as an upstream regulatory partner of MYC in CRPC and demonstrates that NME2-MYC increased activities can predict patients at risk of resistance to Enzalutamide, independent of co-variates. Furthermore, our experimental investigations demonstrate that targeting MYC and its partner NME2 is beneficial in Enzalutamide-resistant conditions and could provide an effective strategy for patients at risk of Enzalutamide resistance and/or for patients who failed Enzalutamide treatment.

Suggested Citation

  • Sukanya Panja & Mihai Ioan Truica & Christina Y. Yu & Vamshi Saggurthi & Michael W. Craige & Katie Whitehead & Mayra V. Tuiche & Aymen Al-Saadi & Riddhi Vyas & Shridar Ganesan & Suril Gohel & Frederic, 2024. "Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC," Nature Communications, Nature, vol. 15(1), pages 1-24, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44686-5
    DOI: 10.1038/s41467-024-44686-5
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