TY - JOUR
T1 - Phenotypic drug screen uncovers the metabolic GCH1/BH4 pathway as key regulator of EGFR/KRAS-mediated neuropathic pain and lung cancer
AU - Cronin, Shane J.F.
AU - Rao, Shuan
AU - Tejada, Miguel A.
AU - Turnes, Bruna Lenfers
AU - Licht-Mayer, Simon
AU - Omura, Takao
AU - Brenneis, Christian
AU - Jacobs, Emily
AU - Barrett, Lee
AU - Latremoliere, Alban
AU - Andrews, Nick
AU - Channon, Keith M.
AU - Latini, Alexandra
AU - Arvanites, Anthony C.
AU - Davidow, Lance S.
AU - Costigan, Michael
AU - Rubin, Lee L.
AU - Penninger, Josef M.
AU - Woolf, Clifford J.
N1 - Publisher Copyright:
© 2022 The Authors.
PY - 2022/8/31
Y1 - 2022/8/31
N2 - Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.
AB - Increased tetrahydrobiopterin (BH4) generated in injured sensory neurons contributes to increased pain sensitivity and its persistence. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme in the de novo BH4 synthetic pathway, and human single-nucleotide polymorphism studies, together with mouse genetic modeling, have demonstrated that decreased GCH1 leads to both reduced BH4 and pain. However, little is known about the regulation of Gch1 expression upon nerve injury and whether this could be modulated as an analgesic therapeutic intervention. We performed a phenotypic screen using about 1000 bioactive compounds, many of which are target-annotated FDA-approved drugs, for their effect on regulating Gch1 expression in rodent injured dorsal root ganglion neurons. From this approach, we uncovered relevant pathways that regulate Gch1 expression in sensory neurons. We report that EGFR/KRAS signaling triggers increased Gch1 expression and contributes to neuropathic pain; conversely, inhibiting EGFR suppressed GCH1 and BH4 and exerted analgesic effects, suggesting a molecular link between EGFR/KRAS and pain perception. We also show that GCH1/BH4 acts downstream of KRAS to drive lung cancer, identifying a potentially druggable pathway. Our screen shows that pharmacologic modulation of GCH1 expression and BH4 could be used to develop pharmacological treatments to alleviate pain and identified a critical role for EGFR-regulated GCH1/BH4 expression in neuropathic pain and cancer in rodents.
UR - http://www.scopus.com/inward/record.url?scp=85137058833&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85137058833&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abj1531
DO - 10.1126/scitranslmed.abj1531
M3 - Article
C2 - 36044597
AN - SCOPUS:85137058833
SN - 1946-6234
VL - 14
JO - Science translational medicine
JF - Science translational medicine
IS - 660
M1 - abj1531
ER -