Liquid-biopsy transcriptomic profiling uncovers molecular mediators of resistance to androgen receptor signaling inhibition in lethal prostate cancer

Abstract

Androgen receptor signaling inhibitors (ARSi) are a mainstay for patients with metastatic castration-resistant prostate cancer (mCRPC). However, patient response is heterogeneous and the molecular underpinnings of ARSi resistance are not well elucidated. Here we performed transcriptome analysis of circulating tumor cells (CTCs) and peripheral blood mononuclear cells (PBMC) in the context of a prospective clinical trial of men with mCRPC treated with abiraterone (Abi) or enzalutamide (Enza). CTC RNA-sequencing identified that RB loss and enhanced E2F signaling along with BRCA loss transcriptional networks were associated with intrinsic ARSi resistance, while an inflammatory response signature was significantly associated with acquired resistance. Transcriptomic analysis of matching PBMCs identified enrichment of inflammasome gene signatures indicative of activated innate immunity at progression, with concurrent downregulation of T and NK cells. Importantly, CTC gene signatures had a significant positive association with circulating immune macroenvironment (CIME) signatures. Taken together, these data demonstrate that liquid biopsy transcriptomics can identify molecular pathways associated with clinical ARSi resistance paving the way for treatment optimization in patients with mCRPC.

Transferrin receptor-based circulating tumor cell enrichment provides a snapshot of the molecular landscape of solid tumors and correlates with clinical outcomes

“…CTCs were enriched via negative depletion of CD45 + -cells and labeled live with antibodies against the cell surface proteins, TfR, EpCAM and CD45 ( Supplementary Figure 4A ). In a different cohort of mCRPC, we recently used the same enrichment protocol and established the prostate cancer origin of CTCs using a stringent transcriptomic pipeline ( 9 ). In the current cohort of 32 mCRPC patients, CTCs were enumerated based on their respective immunophenotypes as TfR + /EpCAM - /CD45 - (hereafter TfR + ), EpCAM + /TfR - /CD45 - (hereafter EpCAM + ) and TfR + /EpCAM + /CD45 - (double positive).…”

“…As CTCs represent tumor cells with intact DNA, RNA and protein content, unlike the fragmented cfDNA, they can provide comprehensive information about the tumors they disseminate from, which can be used in precision oncology. For example, we and others have demonstrated that transcriptomic CTC profiling can identify gene signatures predictive of clinical response to standard of care treatments ( 8, 9 ). However, such a treatment customization approach has not been clinically adopted due to the lack of a uniform CTC isolation platform.…”