Research by a Washington State University-led team of scientists has identified a receptor protein, CHRM1, as a key player in prostate cancer (PC) cells’ resistance to docetaxel (DTX), a chemotherapy drug used to treat advanced cancer that has spread beyond the prostate. The team’s study also showed that in resistant prostate cancer cell lines, and in mice carrying patient-derived drug-resistant prostate tumor xenografts, treatment using the CHRM1 inhibitor drug dicyclomine (Dic) restored docetaxel’s ability to kill cells and stop tumor growth. Dicyclomine is a generic drug that is currently used to treat symptoms of irritable bowel syndrome.
The scientists’ discovery opens the door to new treatment strategies that could overcome prostate cancer drug resistance and ultimately help to extend patient lives. “The effect was pretty dramatic in all the experimental models we tested,” said Boyang Wu, PhD, an associate professor in the WSU College of Pharmacy and Pharmaceutical Sciences. “And because dicyclomine already has a clinical use, this work has immediate translational potential.”
Wu is co-senior author of the team’s published report in Cell Reports Medicine, which is titled “Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.” In their paper the researchers concluded “Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.”
Prostate cancer (PC) is one of the most commonly diagnosed cancers, with more than one million new cases worldwide every year, the authors wrote. And while initial treatments, including androgen deprivation therapy, often lead to a favorable response, most PC patients eventually progress to terminal stage of the disease, known as castration-resistant PC (CRPC). First-line chemotherapy for CRPC is docetaxel (DTX), and this improves patient survival, but the disease will inevitably develop resistance to DTX and progresses to a DTX-refractory state. Patients at this stage have very few therapeutic options afterward,” the team continued, “Thus, there is a significant clinical need to understand the mechanisms associated with DTX resistance for devising a strategy to prolong DTX benefit in CRPC patients.”
Previous research had found that the muscarinic type 1 receptor (CHRM1) is highly expressed in PC clinical samples compared with all other cancer types, and supports PC cell proliferation, migration, and invasion. Studies had also reported that amplification or gain of the CHRM1 gene to be frequent in human CRPC and represent a worse prognostic factor for progression-free survival of PC patients. However, the team noted, “although these earlier studies provided evidence for cholinergic signaling involvement in PC growth and progression, its role in mediating PC cell chemotherapeutic response and resistance has not been defined, nor has the mechanism been elucidated.”
For their study the team further investigated the direct contribution of cholinergic signaling and muscarinic receptors to the development and maintenance of PC docetaxel resistance, and whether the mechanism could be targeting to overcome docetaxel chemotherapy resistance.
Their studies in cell lines and in patient derived xenograft (PDX) mice confirmed activation of the CHRM1 in CRPC cells upon acquiring resistance to docetaxel, which they demonstrated in tumor tissues from PC patients post-docetaxel, compared with pre-docetaxel therapy.
“Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells,” they further noted. “In summary, our data integrating both in vitro and in vivo pre-clinical studies support the conclusion that CHRM1-induced cholinergic signaling is critical for the development and maintenance of DTX resistance in CRPC cells …”.
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.”
The researchers’ say their results support clinical testing to confirm whether combined use of docetaxel and dicyclomine could help overcome treatment resistance in prostate cancer patients. “Importantly, we demonstrated that CHRM1 antagonism in conjunction with DTX enhanced DTX efficacy and effectively restricted the growth of several DTXR lines of CRPC cells and xenografts, including a PDX, which provides a rationale for repositioned use of anti-CHRM1 agents, such as Dic, in combination with DTX for improved chemotherapeutic benefits in PC,” they stated in their report.
This type of combination therapy could also potentially be used for other cancers that are currently being treated with docetaxel, such as breast and lung cancer, Wu suggested. It may also be possible to use the same combination strategy with other similar chemotherapy drugs. In their paper, the team noted, “Other than DTX, we demonstrated prevalent increases in CHRM1 expression by other CRPC therapies, including AR signaling inhibitors and additional chemotherapeutic agents, which raises a possibility that CHRM1 might be activated through a ubiquitous mechanism upon therapeutic pressure.”
