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Why do some prostate cancer drugs fail?

Written by Lauren Robertson, Science Writer

New research suggests some prostate cancer drugs may change how certain prostate tumours function, enabling resistance and ultimately causing treatment to fail.

In a paper published in Nature Communications, Joshi Alumkal and his team studied the transcriptomes of 21 patients with metastatic castration-resistant prostate cancer (CRPC) before and after treatment with the androgen receptor inhibitor enzalutamide. They found that this drug may alter how the tumour functions and even make it more aggressive in some cases.

Analysing androgen

The androgen receptor is the “engine” of prostate cancer cells, and certain male hormones act as its fuel source. For the past 80 years, treatment has focused on altering these hormone levels to treat the cancer. However, often the cancer will develop ways to resist treatment.

More recently, enzalutamide (enza) was developed to treat advanced prostate cancer (CRPC), leading to improved progression-free survival rates. However, one-third of CRPC patients still do not respond to enza treatment, and researchers are unsure why.

Some mechanisms have been suggested, including lineage plasticity – a process by which the tumour evolves to become less dependent on the androgen receptor (AR). But these studies were restricted to DNA mutational profiling, used limited matched samples, and did not look at the transcriptome. To get a better understanding of what is causing resistance in CRPC, Alumkal and his team decided to analyse the transcriptome of male patients before and after enza treatment.

They recruited patients to a longitudinal study, obtaining metastatic biopsies both before treatment, and at the time the tumour showed resistance. All in all, serial biopsies were collected from 21 patients – the largest collection of metastatic biopsies of CRPC before and after treatment to date.

“To understand resistance to drugs, researchers often collect samples from some patients before treatment and from a different group of patients whose tumours are treatment resistant,” said Alumkal. “However, that approach is much less precise because there could be other significant differences between those patients. You can’t pinpoint if the differences have anything to do with drug exposure or have more to do with the tumours just being different to begin with.” By looking at how the tumours change in response to treatment in the same patients, Alumkal and his team could get a much clearer idea of how resistance emerges.

Rewiring a tumour

In 3 of the 21 cases, they found evidence of lineage plasticity – they were no longer reliant on the androgen receptor as an engine.

“We knew that sometimes tumours become fuel-independent and no longer rely on the androgen receptor,” said Alumkal. “These tumours instead turn on a gene expression program more common in nerve cells, rather than prostate cells, and shift to an aggressive form called neuroendocrine prostate cancer.” However, some of the tumours seemed to become fuel-independent for a completely different reason – instead, they were re-wired in a way that was consistent with double-negative prostate cancer (DNPC). In other words, they no longer used the AR, but also did not become neuroendocrine prostate cancer.

The team went on to identify specific genes that were highly expressed in those tumours that eventually become DNPC. The transcription factor E2F1 and pathways linked to tumour “stemness” were highly activated in patients whose tumours showed plasticity. This suggests enza treatment may convert cells to a stem-like cancer state that aids resistance.

They further found a 14-gene signature that is strongly associated with poor survival in independent patient cohorts. However, this signature decreased in the progression biopsies, suggesting it identifies those that are likely to undergo lineage plasticity, rather than those that already have.

More research needed?

The findings from this study are promising and could offer hope for CRPC patients, however the study authors recognise a number of limitations.

In particular, further studies will be needed to evaluate the role of the pathways linked to tumour “stemness” in enza resistance, and to potentially look into targeting these in future drug development initiatives. As Alumkal notes, there is still a lot of work needed to validate the 14-gene signature, mostly because no other studies are available that look at tumour progression in the same patients. However, hopes remain high that their research can prove useful in the future: “It may be possible up-front to identify patients at greatest risk of having their tumour become fuel-independent after treatment with drugs like enzalutamide,” he said.