Lineage plasticity is a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors potentially lead to the accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. However, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identifies ROR2 as the top upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem-cell-like and neuronal networks. Mechanistically, ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.
Cell reports. 2023 Aug 07 [Epub ahead of print]
Nakisa Tabrizian, Shaghayegh Nouruzi, Cassandra Jingjing Cui, Maxim Kobelev, Takeshi Namekawa, Ishana Lodhia, Amina Talal, Olena Sivak, Dwaipayan Ganguli, Amina Zoubeidi
Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada., Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada., Department of Urologic Sciences, The University of British Columbia, Vancouver, BC V5Z 1M9, Canada; Vancouver Prostate Centre, Vancouver, BC V6H 3Z6, Canada. Electronic address: .