RNA-Seq identifies possible cause of resistance to prostate cancer treatment

A Roswell Park-led research team has linked the development of castration-resistant prostate cancer and resistance to treatment to a lack of androgen receptor expression in prostate cancer cells, identifying a new therapeutic target.

 A collaborative research team has linked the development of castration-resistant prostate cancer and resistance to treatment to a lack of androgen receptor (AR) expression in prostate cancer cells, identifying a new therapeutic target for one of the deadliest forms of cancer among men. Results of this research, which was led by scientists at Roswell Park Comprehensive Cancer Center, were published today in the journal Nature Communications.

Prostate cancer is one of the most common and treatable types of cancer in men. Most patients respond well to hormone therapy or chemotherapy, and five-year survival rates have reached nearly 100% thanks to advances in detection and treatment. However, prostate cancer remains the second-leading cause of male cancer deaths, because those with more advanced or aggressive forms of the disease eventually experience progression or recurrence despite treatment.

For men with advanced disease and tumors that cannot be surgically removed, standard therapy involves drugs that target and block AR, a protein that binds to androgens (male hormones). AR-targeted therapies stop or inhibit the growth of prostate cancer cells, but for unknown reasons, their effectiveness is usually short-lived. Within a year or two of antiandrogen therapy, many patients will develop castration-resistant prostate cancer, an aggressive and treatment-resistant form of the disease.

In an effort to uncover the mechanisms of treatment resistance and progression in prostate cancer, a team of scientists led by Dean Tang, PhD, Chair of Pharmacology and Therapeutics at Roswell Park Comprehensive Cancer Center, in collaboration with scientists at other cancer centers and research institutions in the United States and China, examined AR expression patterns in 89 patients with castration-resistant prostate cancer and found three distinct types: AR in the nucleus of the cancer cell, AR in both the nucleus and cytoplasm, and near or complete absence of AR from all parts of the cell.

BCL-2 inhibitor prevents AR+/hi LNCaP 2° CRPC

 rna-seq

a Experimental scheme of RNA-Seq in LNCaP models. b GSEA showing that both primary (pri) and secondary (sec) LNCaP CRPC are enriched in gene sets upregulated in ADT-resistant patient CRPC. All genes differentially expressed in 1° and 2° CRPC vs. AD tumors were used in GSEA against the upregulated genes in the Rajan data set. c Both LNCaP 1° CRPC (vs. AD) and LNCaP 2° CRPC (vs. AD) DEGs positively associate with the CRPC-NE gene expression profile. All genes differentially expressed in 1° and 2° CRPC vs. AD tumors were used in GSEA against the entire list of genes expressed in the Beltran data set. d Heat map of the stem cell associated genes altered in Enza-resistant LNCaP 2° (Sec) CRPC compared with LNCaP 1° (Pri) CRPC. BCL-2 was highlighted with a red arrow. e GSEA showing that genes preferentially expressed in LNCaP 2° CRPC (vs. 1° CRPC) were enriched in BCL-2 targets. f Enza induces BCL-2 expression in primary patient PCa cells. WB analysis of BCL-2 in HPCa cells freshly prepared from 3 primary tumors and treated with Enza for 72 h. g BCL-2 promotes LNCaP cell holoclone growth in Enza-containing medium. P value was determined using paired Student’s t-test (mean ± SD). h BCL-2 promotes rapid LNCaP AD tumor growth in intact male NSG mice. Presented is the median tumor (T) volume (note that the majority of tumors developed in the CTL group were very small resulting in low median tumor volumes shown here). i BCL-2 is a critical therapeutic target for AR+/hi LNCaP 2° CRPC. Shown on top is a timeline of the therapeutic experiment for LNCaP CRPC with 4 groups of treatment (all i.p injections; combo = Enza + RU486 + ABT-199). Shown below are endpoint tumors with weight and incidence indicated and P values for tumor incidence (χ2 test)

Further research confirmed that cells lacking AR did not respond to treatment with enzalutamide (brand name Xtandi), an AR blocker commonly used to treat patients with castration-resistant prostate cancer. These prostate cancer cells were also more likely than AR-containing cells to grow, regenerate and proliferate. Through deep RNA-Seq analysis, the team identified BCL-2, a stem-cell-enriched prosurvival molecule, as a critical regulator and important therapeutic target in castration-resistant prostate cancer cells.

“In order to survive the pressure of chemical castration and antiandrogen therapy, prostate cancer cells overexpress, redistribute or lose androgen receptor,” explains Dr. Tang, the senior author of the study. “Our study offers new proof-of-principle therapeutic strategies to not only treat advanced and metastatic prostate cancer but also prevent castration resistance.”

The research team also reports new evidence that combination treatment with enzalutamide and ABT-199 (brand name Venetoclax), a newly FDA-approved BCL-2 inhibitor, markedly inhibits experimental castrate-resistant prostate cancer. Dr. Tang has initiated a phase Ib/II clinical trial based on these findings, in collaboration three Roswell Park clinical colleagues: Gurkamal Chatta, MD, James Mohler, MD, and Igor Puzanov, MD, MSCI, FACP, who are also co-authors on the new published research.

Source – PR Newswire

Li Q et al. (2018) Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses. Nat Comm [Epub ahead of print]. [article]

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