TY - JOUR
T1 - Mechanism-centric regulatory network identifies NME2 and MYC programs as markers of Enzalutamide resistance in CRPC
AU - Panja, Sukanya
AU - Truica, Mihai Ioan
AU - Yu, Christina Y.
AU - Saggurthi, Vamshi
AU - Craige, Michael W.
AU - Whitehead, Katie
AU - Tuiche, Mayra V.
AU - Al-Saadi, Aymen
AU - Vyas, Riddhi
AU - Ganesan, Shridar
AU - Gohel, Suril
AU - Coffman, Frederick
AU - Parrott, James S.
AU - Quan, Songhua
AU - Jha, Shantenu
AU - Kim, Isaac
AU - Schaeffer, Edward
AU - Kothari, Vishal
AU - Abdulkadir, Sarki A.
AU - Mitrofanova, Antonina
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85181883410&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-44686-5
DO - 10.1038/s41467-024-44686-5
M3 - Article
C2 - 38191557
AN - SCOPUS:85181883410
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 352
ER -