Lineage plasticity-driven resistance and novel combination therapy

During my postdoctoral training, I identified a novel mechanism of antiandrogen resistance wherein tumors with TP53 and RB1 alterations undergo lineage plasticity, or “identity fraud.” The cancer cells with lineage plasticity can “transdifferentiate” away from a fixed luminal cell lineage to a multi-lineage, progenitor-like status that no longer depends on androgen-receptor signaling. This lineage plasticity is enabled by up-regulation of transcription factor SOX2 and can be reversed by knocking down SOX2.

Direct pharmacologic inhibition of SOX2 is not currently feasible, but preventing SOX2 transcriptional upregulation or inhibiting the downstream pluripotency network are two potential therapeutic avenues.

Our goal is to identify the exact mechanism of SOX2 activation and the critical components of its downstream regulatory network: key steps towards novel approaches for clinical intervention.