MCL1 Identified as Key Resistance Driver in Castration-Resistant Prostate Cancer

A new study identifies the protein MCL1 as a primary driver of drug resistance in aggressive prostate tumours. Targeting this mechanism may restore sensitivity to standard therapies and improve survival rates.

Defining Risks in Castration-Resistant Prostate Cancer

Advanced disease often stops responding to androgen receptor (AR) targeting. This state, known as castration-resistant prostate cancer (CRPC), presents a lethal challenge. Tumours evolve. They find survival pathways that bypass the androgen receptor entirely or adapt to thrive despite blockade. Current standard-of-care drugs like enzalutamide often fail when these alternative routes open up. The clinical gap lies in identifying exactly how specific tumour subtypes evade treatment before resistance becomes irreversible.

Subtyping for Precision

Researchers utilised CRISPR-Cas9 screens across multiple cell lines to map essential genes. They distinguished between AR-dependent and AR-independent survival mechanisms. By integrating RNA sequencing data from major cohorts (TCGA-PRAD, DKFZ), the team classified tumours into three distinct molecular clusters. 'Cluster 3' emerged as the most dangerous. This subtype correlates with the worst prognosis, higher Gleason grades, and advanced metastasis. It represents a distinct biological profile that demands specific intervention rather than a blanket approach.

The Mechanism: MCL1 Upregulation

How does Cluster 3 survive? The study points to MCL1. While AR-high signatures rely on cell cycle pathways, AR-low signatures shift towards oxidative phosphorylation and mTOR signalling. Crucially, MCL1 expression spikes in enzalutamide-resistant cell lines. It acts as an anti-apoptotic shield, preventing cell death even under drug pressure. The data indicates that AR-dependent cells show marked sensitivity to the MCL1 inhibitor UMI-77. Functional validation confirmed that knocking down MCL1 halts proliferation in resistant cells, effectively removing the tumour's safety net.

Strategic Implications

This defines a clear therapeutic target. The identification of Cluster 3 provides a prognostic marker for patients likely to fail standard hormone therapy. More importantly, the results suggest a combination strategy. Pairing AR-targeting agents with MCL1 inhibitors could block both the primary driver and the escape route. While this represents pre-clinical data, the strong correlation between Cluster 3 signatures and poor clinical outcomes highlights the urgency of testing MCL1 inhibitors in human trials. The findings offer a concrete path to addressing adaptive resistance.