Prostate cancer is the second most common cancer in the United States and the fourth most common cancer in the world. Researchers have identified a receptor protein known as CHRM1 that plays a key role in the resistance of prostate cancer cells to docetaxel, a chemotherapy drug commonly used to treat advanced cancer that has metastasized. The discovery opens the door to new strategies that could overcome this resistance. This could ultimately help prolong the lives of people with prostate cancer. Conducted by a team of scientists at Washington State University, the study demonstrated that blocking CHRM1 in resistant prostate cancer cell lines and a patient-derived resistant tissue-based animal model restored docetaxel’s ability to kill cells and stop the growth of the tumor.
The researchers used dicyclomine, a drug that selectively inhibits the activity of CHRM1. Dicyclomine is already on the market as a generic drug and is currently used to treat the symptoms of irritable bowel syndrome. Published in the magazine Cell Reports Medicine, the researchers’ findings support clinical trials to confirm whether the combined use of docetaxel and dicyclomine could help overcome treatment resistance in prostate cancer patients. Resistance to docetaxel can develop in prostate cancer after about six months of treatment. Chemotherapy drugs such as docetaxel are among the very few options available for patients with hormonally obtained castration-resistant prostate cancer (CRPC). In addition to testing resistant tumor cell lines, the research team also tested cells that still responded to docetaxel.
They found that using dicyclomine to block CHRM1 in these cells made docetaxel more efficient at killing them. This demonstrates that prostate cancer patients could potentially benefit from a combined treatment strategy even before resistance to docetaxel develops. Meanwhile, despite advances in drug discovery and repurposing, there is potential to take advantage of existing data and improve upon prior knowledge by combining efforts from other fields. For example, now researchers at Rutgers have devised a strategy that could make the treatment work longer. For the study, scientists developed computational algorithms to find out why the popular drug enzalutamide (brand name Xtandi) never works for some patients and why it eventually stops working in others.
The researchers analyzed advanced data from prostate cancer patients to map interactions between molecular pathways and their upstream transcription factors in prostate cancer cells. Their focus was on the MYC pathway because of its known role in prostate cancer. They found that another protein and transcription factor, NME2, works closely with c-Myc in advanced prostate cancer cells that resist enzalutamide and continue to spread. Analysis of medical records found that patients with elevated levels of c-Myc and NME2 were five times less likely than others to benefit from the drug. The analysis also found that protein levels increased significantly in most patients who responded to the drug only temporarily.
The researchers collaborated with colleagues at Northwestern University to confirm these findings with experiments on laboratory mice and tumor tissue. Their work demonstrated once again that elevated levels of c-Myc and NME2 were associated with a poor response to enzalutamide, both in tissue samples and in live mice, and that c-Myc and NME2 could increase in response to use of enzalutamide, which explains why the drug might eventually stop working. But there was a silver lining: Reducing levels of NME2 and, therefore, c-Myc restored enzalutamide’s effectiveness in tumors that had become resistant to its effects. The data indicate that patients with elevated levels of c-Myc and NME2 resistant to enzalutamide may still respond to alternative drugs, such as abiraterone (Zytiga), and could significantly benefit from therapeutic targeting of MYC, restoring the efficacy of enzalutamide and making it work longer for these patients.
Finally, new molecular targets (proteins or enzymes) can be exploited once their biology is understood or an unexpected cellular phenomenon is observed and the molecular correlations to be exploited in the therapeutic field are found. Researchers and clinicians know that androgen receptor (AR-alpha)-mediated cell signaling is an important factor in the progression of CRPC while only a fraction of the tumor becomes AR-negative. Scientists have discovered that to neutralize AR-alpha you can not only use drugs, it also encourages cells to get rid of it. This can be done by inhibiting an enzyme called N-myristoyl transferase (NMT1), which attaches myristic acid tails to proteins so that they can anchor themselves to cell membranes. Scientists thus synthesized (1R,2R)-LCL204, a drug that inhibited global protein myristoylation.
After this effect, the protein levels, nuclear translocation, and transcriptional activity of full-length AR or its variants in PCa cells were suppressed. This was due to increased degradation of AR-alpha mediated by the ubiquitin-proteasome axis. Knocking down NMT1 levels inhibited tumor growth and tumor cell proliferation. This research illustrates a new function of NMT1 and provides a potential strategy for the treatment of CRPC. And not only that: it confirms that testosterone hormone receptors do not roam free in the cytoplasm as previously thought. It has long been known that steroid receptors can attach to biological membranes, although the reason for this has not been understood. The hypothesis had been put forward that they waited for the entry of the hormone (estrogens, androgens, etc.), and then detached and migrated into the nucleus.
This hypothesis was put aside when it was discovered that receptors for sex hormones also exist outside cells, which mediate rapid effects not directed at DNA but which can, however, prepare the “biochemical terrain” for future gene transcription. Furthermore, myristoylation also belongs to G proteins coupled to surface receptors, including oncogenic G proteins such as Rap1, Rac1 and the famous H-Ras, against which research has developed very specific inhibitors. These drugs, however, struggle to be effective in clinical trials for reasons that are yet to be understood. Scientists do not know whether blocking all global myristoylation and seeing the degradation of AR-alpha involves the hand of a G protein like H-Ras, but defective.
The Ras/MAP-kinase dialogue with testosterone receptors has been demonstrated for some time and in any case the discovery deserves further pharmacological and therapeutic investigations. Also opening up curiosities derived from new molecular notions that can lead to the rediscovery of set aside mechanisms, but which are worth exploiting in the name of oncological therapies aimed at treating patients.
By Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific publications
Wang J, Wei J et al. Cell Reports Med 2024 Jan; 5:101388.
Panja S et al. Nature Common. 2024 Jan; 15(1):352.
Alsaidan OA, Onobun E et al. Prostate. 2024; 84(3):254-68.
Mullen SA, Das D et al. Prostate. 2024; 84(3):277-84.