Why prostate cancer treatment may fail

Disease and treatment 2. okt 2022 2 min Professor,PhD, MSc Karina Dalsgaard Sørensen Written by Kristian Sjøgren

The latest treatments against prostate cancer require six functioning genes to be present to be effective. Unfortunately, cancer cells can resist these treatments by destroying the function of the genes. Research in Denmark opens up the possibility of screening men with prostate cancer to determine who might benefit from specific treatments and who might not.

Doctors have many drug options for treating men with prostate cancer.

In the late stages of the disease, doctors have to take drastic actions, including using some of the newest anticancer drugs, including treatment with poly(ADP-ribose) polymerase (PARP) inhibitors. They disrupt the repair mechanisms of cells, leading to the accumulation of toxins in the cancer cells, which theoretically should kill them.

Unfortunately, the cancer cells often develop resistance to treatment with PARP inhibitors, and then the doctors have few options.

A new study shows how cancer cells develop such resistance. The research could potentially identify who might benefit from treatment with PARP inhibitors and who might not and may also pave the way for developing new combination therapy that could leave the cancer cells defenceless.

“With the focus on benefitting patients, our results may create the basis for new clinical trials to determine how to optimally use PARP inhibitors for men with prostate cancer and what to do if the treatment is not effective,” explains a researcher behind the study, Karina Dalsgaard Sørensen, Professor, Department of Clinical Medicine, Aarhus University and Department of Molecular Medicine, Aarhus University Hospital.

The research has been published in Oncogene.

Editing the genes of cancer cells

The researchers sought to determine what happens at the genetic level when cancer cells switch from being sensitive to PARP inhibitors to being resistant.

They therefore investigated the effects of knocking out 20,000 individual genes in cancer cells using CRISPR-Cas9 gene-editing technology to disable each gene. The researchers then tested how this affected the cancer cells’ resistance to PARP inhibitors.

Six genes associated with cancer resistance

The results show that six specific genes are required for PARP inhibitors to have the desired effect on prostate cancer cells.

Disrupting the function of any of these six genes limits the effectiveness of PARP inhibitors.

Karina Dalsgaard Sørensen envisions that a PARP inhibitor might initially work and kill the prostate cancer cells. However, because these cells slowly mutate, the genes are knocked out and the cancer cells thereby become resistant and the treatment no longer works.

“This advances knowledge on how effective PARP inhibitors are and how we can better understand why treatment works for some but not others,” says Karina Dalsgaard Sørensen.

Genes have an important role in cell death

The six genes involved in developing resistance to treatment in prostate cancer are not very well known, and the literature has only said that they probably play a role in repairing cells.

The researchers therefore set out to investigate the function of one of the genes, ARH3, and found that it plays an important role in autophagy, a mechanism defective cells use to signal that they no longer work properly and then the immune system destroys them.

When ARH3 is disabled, the affected (cancer) cells stop signalling and the immune system is not activated.

ARH3 apparently also plays an important role in the cancer-inhibiting function of PARP inhibitors, and in further experiments the researchers showed that when they reactivated autophagy, the cancer cells again became sensitive to PARP inhibitors.

“This indicates that there may be potential for men with prostate cancer and mutations in some of these genes to combine PARP inhibitors with other drugs that can re-establish the function of the genes so that the cancer cells become sensitive again and can be suppressed,” explains Karina Dalsgaard Sørensen.

Screening for effectiveness of PARP inhibitors

Karina Dalsgaard Sørensen sees potential for this discovery to lead to better diagnostic tools that can identify the people with certain mutations who might not benefit from PARP inhibitors.

In these cases, other drugs can be tried right away instead of waiting to discover that the PARP inhibitors do not work.

In fact, the researchers and doctors from Aarhus University Hospital are recruiting participants for a clinical trial in which they will take blood samples from men with prostate cancer to identify those for whom PARP inhibitors are not effective.

If they can do this, the next series of trials could aim to do something about it.

“We will start by observing and then see whether this provides a basis for changing something. In addition, investigating the function of these genes will also be useful to learn more about the mechanisms behind prostate cancer and treatment resistance,” concludes Karina Dalsgaard Sørensen.

A genome-wide CRISPR-Cas9 knockout screen identifies novel PARP inhibitor resistance genes in prostate cancer” has been published in Oncogene. In 2016, the Novo Nordisk Foundation awarded a grant to Karina Dalsgaard Sørensen for the project Genome-wide CRISPR-Cas9 Screening for Drug Resistance Mechanisms and Identification of Novel Predictive and Monitoring Biomarkers for Castration-resistant Prostate Cancer.

Prostate cancer (PC) is the most commonly diagnosed malignancy and the third leading cause of cancer-related death in males in Western countries, incl...

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