New research has revealed that the receptor protein known as CHRM1 was identified as a key driver for docetaxel-resistant prostate cancer. Led by a team of scientists at Washington State University, the study showed that inhibiting CHRM1 restored docetaxel’s ability to kill cells and stop tumor growth. The researchers suggest blocking CHRM1 might help overcome resistance to docetaxel, one of the main chemotherapy drugs for advanced prostate cancer. The research is published in Cell Reports Medicine.
“CHRM1 has been known to have a role in promoting prostate cancer growth and progression, but its specific role, function, and mechanism has not been well understood,” explains co-senior author Boyang (Jason) Wu, of the WSU College of Pharmacy and Pharmaceutical Sciences. But its utility has not been studied in the context of chemotherapy resistance. “In this paper, we have identified it as a potential therapeutic target in chemotherapy resistance prostate cancer.”
The researchers chose to study docetaxel-resistant prostate cancer since docetaxel is the first-line therapeutic drug for advanced prostate cancer. “We need to find alternative treatment options for these patients,” adds Wu.
In their study, The team found that both genetic and pharmacological inactivation of CHRM1 restored docetaxel efficacy in resistant cells. The researchers inhibited CHRM1 pharmacologically with dicyclomine, a drug that selectively inhibits CHRM1 activity, which is already on the market as a generic drug and is currently used to treat symptoms of irritable bowel syndrome.
“We saw that CHRM1 inactivation could be utilized as a target for overcoming docetaxel resistance,” says Wu. After silencing CHRM1 expression with dicyclomine, docetaxel sensitivity was restored in resistant cells. These findings were consistent in cell line models and animal models, including a patient-derived xenograft model using docetaxel-resistant patient tissue samples.
The team focused on CHRM1 after genomic profiling and bioinformatics studies revealed that the acetylcholine signaling pathway is enriched in docetaxel-resistant prostate cancer cells compared to sensitive controls.
“We speculated that acetylcholine signaling has a role in docetaxel resistance,” adds Wu. “Further studies showed that acetylcholine secretion as well as CHRM1 are elevated in the cells, which prompted us to initiate this study.”
Based on these findings the team plans to pursue two future directions. One is to see whether this combination can be applied to other types of cancers, like breast and lung, where docetaxel is routinely used. Another line is to test combination treatment of dicyclomine with other taxol-based chemotherapy drugs.
In addition to testing resistant cancer cell lines, the research team also tested cells that still responded to docetaxel treatment. They found that using dicyclomine to block CHRM1 in these cells made docetaxel more efficient at killing them. Wu said that this shows that prostate cancer patients could potentially benefit from a combination treatment strategy even before docetaxel resistance develops.
“What this suggests is that the lowest effective dose of docetaxel may be lower when the drug is combined with dicyclomine, compared to when docetaxel is used alone,” Wu said. “Being able to use a lower dose could help reduce unwanted side effects and make treatment more manageable for patients.”
