CDK4/6 inhibitors (CDK4/6i, CDK4/6 inhibitors) can improve the survival rate of patients with estrogen receptor-positive (ER+) breast cancer. However, patients treated with CDK4/6i eventually develop drug tolerance and disease progression. Loss-of-function alterations in RB1 confer resistance to CDK4/6i, but optimal therapies for these patients have yet to be developed.
Recently, in a research report titled "PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer" published in the international magazine Nature Communications, Scientists from Southwestern Medical Center and other institutions in the United States have discovered through research that turning off a special gene called PRMT5 may block the continued growth of estrogen receptor-positive breast cancer cells when resistance to standard treatment with CDK4/6 inhibitors develops. Relevant research results are expected to help develop new treatments for metastatic ER+ breast cancer.
ER+ breast cancer is the most common subtype of breast cancer and causes the most deaths each year. Researcher Professor Lin said that combining anti-estrogen therapy with drugs that inhibit PRMT5 may eventually provide a new treatment method for patients who are resistant to CDK4/6 inhibitors. Approximately 700,000 women worldwide die from breast cancer every year, mainly from a subtype of breast cancer that carries estrogen receptors (ERs) and metastasizes. Clinicians are increasingly treating metastatic ER+ breast cancer by combining drugs that degrade or block estrogen receptors on breast cancer cells with CDK4/6 inhibitors. These combination therapies promote the inactivation of proteins that are important for breast cancer cells to divide and reproduce.
| Cat.No. | Product Name | Price |
|---|---|---|
| CSC-DC002874 | Panoply™ Human CDK4 Knockdown Stable Cell Line | Inquiry |
| CSC-RT1960 | CDK4 Knockout Cell Line-HeLa | Inquiry |
| CSC-RT2742 | Human CDK4 Knockout Cell Line-HCT116 | Inquiry |
| CSC-SC002874 | Panoply™ Human CDK4 Over-expressing Stable Cell Line | Inquiry |
| AD03471Z | Human CDK4 adenoviral particles | Inquiry |
| LVIM011Z | Human CDK4 Lentivirus (CMV, Puro) | Inquiry |
| LVIM012Z | Human CDK4 Lentivirus (CMV) | Inquiry |
| LVIM023Z | EF1a-hCDK4(GFP, Puro) Lentiviral Particles | Inquiry |
| LVIM024Z | EF1a-hCDK4(RFP, Bla) Lentiviral Particles | Inquiry |
| CLKO-1388 | CDK6 KO Cell Lysate-HeLa | Inquiry |
| MiUTR1M-02869 | CDK6 miRNA 3'UTR clone | Inquiry |
| AD00079Z | Human CDK6 adenoviral particles | Inquiry |
| AD03478Z | Human CDK6 adenoviral particles | Inquiry |
| CDCB162208 | Chicken CDK6 ORF Clone (NM_001007892) | Inquiry |
| CSC-RT1541 | Human CDK6 Knockout Cell Line-HeLa | Inquiry |
| LV08654L | human CDK6 (NM_001259) lentivirus particles | Inquiry |
| SHH260701 | shRNA set against Mouse CDK6 (NM_009873.2) | Inquiry |
Although CDK4/6 inhibitors can block cancer progression and prolong patient survival, they also have the disadvantage that over time, nearly all tumors stop responding to these drugs, which leaves patients with very limited treatment options. Previous research results have shown that an increasing number of tumors that are resistant to CDK4/6 inhibitors will lose the function of the RB1 gene. Therefore, researchers currently urgently need to find new therapies to treat metastatic ER+ breast cancer that is resistant to CDK4/6 inhibitors. In this study, researchers used CRISPR gene editing tools to edit and delete the RB1 gene in two ER+ breast cancer cell lines through joint research, thereby becoming resistant to all three FDA-approved CDK4/6 inhibitors.
Figure 1. Combination of fulvestrant and pemrametostat synergistically inhibits growth of ER+/RB1-deficient breast cancer in vitro and in vivo. (Lin, Chang-Ching, et al. 2024)
The researchers then screened more than 19,000 other genes, looking for those that play important roles in cell growth and survival. Finally, they zeroed in on the PRMT5 gene, which is involved in the progression of multiple cancer types, including breast cancer. They are also currently developing new pharmaceutical inhibitors. When researchers use genetic techniques to reduce the levels of the protein produced by PRMT5 or use PRMT5 inhibitors in clinical development, cells become stuck in a part of the cell cycle called the G1-S transition. During this process, DNA is often replicated before the cell divides.
Further investigation showed that PRMT5 may help regulate the expression of a series of genes involved in DNA replication. When using inhibitors and drugs that degrade ERs in mice bearing RB1-knockout ER+ tumors, the dual therapy may be more effective at blocking tumor growth than single therapy. Researchers Lin said they hope to test the efficacy of this combination therapy in treating ER+ breast cancer patients in future clinical trials.
Taken together, the findings highlight that ER and PRMT5 blockade may serve as a potential therapeutic strategy to overcome resistance to CDK4/6 inhibitors in ER+/RB-deficient breast cancer.
Reference
Lin, Chang-Ching, et al. "PRMT5 is an actionable therapeutic target in CDK4/6 inhibitor-resistant ER+/RB-deficient breast cancer." Nature communications 15.1 (2024): 2287.