Abstract NG06: CHD1-loss confers AR targeted therapy resistance via promoting cancer heterogeneity and lineage plasticity

BACKGROUND: Pharmacological targeting of driver alterations in cancer has resulted in many clinical successes but is limited by concurrent or novel genomic alterations. One potential explanation for this heterogeneity is the presence of additional genomic alterations which modify the degree of dependence on the targeted driver mutation. Metastatic prostate cancer (mPCa) serves as a relevant example, where the molecular target is the androgen receptor (AR) which functions as a lineage survival factor of luminal prostate epithelial cells. Next generation AR targeted therapies such as abiraterone, enzalutamide and apalutamide have significantly improved the survival of men with mPCa and achieved exciting clinical success. However, resistance to these therapies with disease progression is unfortunately inevitable, with intrinsic resistance noted in around 30% patients and acquired resistance in most patients. Therefore, there is an unmet need to understand the mechanism of therapy resistance to AR targeted therapies and identify novel therapeutic approach to prevent or reverse resistance. Previously, we have revealed that the deactivation of two genes, TP53 and RB1, confers AR targeted therapy resistance through a novel mechanism by which tumor cells acquire lineage plasticity and transit to a multi-lineage, progenitor-like state no longer dependent on AR. This lineage plasticity and resistance is enabled by the activation of SOX2 and is completely reversible by knocking down SOX2. This observation not only adds clarity to the mechanism of resistance, but also suggests that appropriate clinical interventions of lineage plasticity may be a potential avenue to overcome resistance. However, there is only 10% mPCa patients carrying homozygous deletions in both TP53 and RB1 loci, thus additional genomic alterations may be responsible for the resistance in other patients. METHODS: To gain functional insight into the genes impacted by the copy number alterations in mPCa, we screened 4234 short hairpin RNAs (shRNAs) targeting 730 genes often deleted in human prostate cancer (annotated from a survey of six prostate cancer genomic datasets) for hairpins that confer in vivo resistance to the antiandrogen enzalutamide, in a well credentialed enzalutamide-sensitive xenograft model LNCaP/AR. More than 350 resistant tumors emerged by 16 weeks of xenografting and the genomic DNA of these tumors were extracted and sequenced to determine the enrichment of specific shRNAs compar