Prostate cancer is the most common cancer among men. Many patients can live long lives due to early detection and treatment with androgen deprivation therapy. Androgen deprivation therapy has been the mainstay of prostate cancer treatment for decades. The goal of this therapy is to reduce the levels of androgens that stimulate prostate cancer cell growth through either surgical or medical approaches that target androgen receptor signaling. Androgen deprivation therapy greatly improves survival, but almost always leads to recurrent disease called castration-resistant prostate cancer. Scientists have discovered that resistance is primarily due to re-activation of androgen receptor signaling through different mechanisms, and they developed new drugs, such as enzalutamide and abiraterone, to overcome this resistance. Unfortunately, patients also eventually develop resistance to these drugs in a relatively short period of time. Several resistance mechanisms to these drugs have been identified, but these modifications are not present in all patients, suggesting that additional resistance mechanisms exist.
In a new research published in Science Translational Medicine, Moffitt Cancer Center researchers reveal a mechanism by which prostate cancer cells become resistant through molecular modification of the androgen receptor protein and identify a potential treatment approach that could overcome this resistance. The team, in collaboration with scientists at Washington University in St. Louis, wanted to identify alternative resistance mechanisms to enzalutamide and abiraterone in prostate cancer patients. They performed a series of laboratory experiments focused on the molecular modifications of the androgen receptor and its interactions with other proteins and DNA. They discovered that the androgen receptor becomes chemically modified at two distinct sites. First, a phosphate group is added to the androgen receptor protein by protein kinase ACK1. This chemical modification permits a second modification, during which an acetyl chemical group is added (acetylation). This modification occurs on a location of the androgen receptor that enables it to become active, even in the presence of enzalutamide.
These combined events result in a positive feedback loop during which the androgen receptor further increases levels of itself, as well as the ACK1 protein. The researchers demonstrated that treatment of enzalutamide/abiraterone-resistant prostate tumors in mice with a Moffitt-designed ACK1 inhibitor called (R)-9b that targets ACK1 suppressed tumor growth, and reduced expression levels of ACK1, the androgen receptor and additional key genes regulated by the androgen receptor. Importantly, the expression level of ACK1 and the modified androgen receptor were higher in tissue samples from patients with prostate cancer than normal prostate tissue, and their expression increased throughout cancer progression. Scientists think that the identification of an ACK1 kinase inhibitor that has the ability to thwart both the modifications, and the fact that an ACK1 inhibitor has not yet advanced to clinical trials, these data could open a new therapeutic modality for recurrent castration-resistant prostate cancer patients, a currently unfulfilled need.
But ACK1 is no the only kinase involved in prostate cancer biology or drug resistance. MAPK downstream ribosomal S6 kinase (Rsk1) has been shown to play a key role in cellular resistance to endocrine therapy in prostate cancer, through its regulation of YB-1/androgen receptor (AR) signaling. This protein kinase drives part of th mitogenic effects of growth factors in normal anc in cancer cell. Yet, the presence of Rsk1 phosphorylation consensus sites in proteins different than those incolved in the ribosomal newtwork, led researchers to think that this protein kinase has additional roles possibily controlling other cellular substrates. Inhibitors against Rsk1 and the related Rsk2 have been developed and applied to basic science to unravel the downstream signaling of mitogenic (MAP) kinases. Examples are SL-101, BRD7389 and PF4708671. However PMD-026, an oral first-in-class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor that may be clinically relevant.
Scientists from Kyushu University in Japan investigated the effect of PMD-026 on YB-1/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. They used castration-resistant prostate cancer 22Rv1 cells express high-level AR variants as a model: when they were exposed to the drug, this decreased phosphorylation of YB-1 transcription factor as well as AR V7 mRNA and AR variant expressions in these cells. PMD-026 suppressed cell proliferation alone and in combination with the second-generation antiandrogens enzalutamide and darolutamide by inducing G2/M arrest and cell death. PMD-026 plus enzalutamide were not synergistic, though they coworked for an enhanced cytotoxicity. The effect was also observed in a xenografted model of mouse. The drug is ready to enter an exploratory clinical trial within this year and the process will be expedited, since there are already data form other clinical trials where PMD-026 has been proven effective for other tumoral forms.
- edited by Dr. Giafrancesco Cormaci, PhD; specialist in Clinical Biochemistry.
Sawant M et al. Sci Translati Med 2022; 14(649):eabg4132.
Ushijima M et al. Cencer Sic. 2022 May; 113(5):1731-1738.
Cancer Res. 2022 Jan 1; 82(1):155-168.
Sci Reports. 2019; 9(1):18637.
Dott. Gianfrancesco Cormaci
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