Researchers are targeting RNA splicing machinery to develop novel cancer treatments
Alterations in RNA processing have emerged as a new cancer hallmark and a promising target for cancer therapies. Splicing, polyadenylation, and other steps in RNA processing are crucial for the correct expression of genes and are tightly controlled in normal cells.
“Thousands of RNA splices have been recognized in multiple forms of cancer,” said Olga A. Anczuków, PhD, Associate Professor at The Jackson Laboratory for Genomic Medicine. “Alterations in splicing can result in aberrations in isoforms and all of the hallmarks of cancer we have come to recognize. We can also see splicing-driven alterations in drug responses to HER2-targeting antibodies, CD19 CAR T-cell therapy, and other therapies.”
Anczuków chaired the Annual Meeting symposium Targeting RNA Splicing in Cancer and the Immune System on Sunday, April 16. The session can be viewed on the virtual meeting platform by registered meeting participants through July 19, 2023. The talks in this session examined strategies to target splicing and to leverage new knowledge about splicing factors and isoforms expressed in cancers to develop new therapeutic approaches.
The splicing regulation (SR) protein family comprises 14 SR and SR-like proteins that are frequently altered in breast and other tumors, Anczuków explained. The SR-like protein TRA2β, for example, regulates cell invasion in triple-negative breast cancer (TNBC) models and in human tumors. Knock down of TRA2β did not prevent primary tumors, but prevented metastasis in animal models. High levels of TRA2β were associated with poor outcomes in women with breast cancer.
The MYC gene promotes breast cancer, at least in part, by enhancing alternative pro-tumor splicing factor (SF) genes. These SF genes act in combinations, or modules. A module of three SF genes — SRSF2, SRSF3, and SRSF7 — is a pan-cancer signature of MYC-active tumors, Anczuków said.
SF homeostasis contributes to physiological cell functions, and dysregulation of SF homeostasis is a hallmark of cancer. Splice-switching antisense oligonucleotides (ASOs) can target TRA2β splicing to increase cell death and decrease proliferation in TNBC models without affecting cell death in non-transformed tissue.
“There is a therapeutic window of opportunity with ASOs,” Anczuków said. “We need to optimize dosing and delivery before moving into the clinic.”
Targeting the RNA spliceosome
MYC is the most commonly dysregulated transcription factor in cancer and is hyperactive in more than 65 percent of TNBCs. But like many oncogenes, MYC has both pro- and antitumorigenic effects, said Trey Westbrook, PhD, Professor of Molecular and Human Genetics and of Biochemistry and Molecular Biology at the Baylor College of Medicine Therapeutic Innovation Center.
MYC-induced stresses can trigger oncogenic stress and cell death to inhibit tumorigenicity, he continued. Oncogenic MYC induces stress in many RNA metabolic pathways, and MYC-driven cancer models are sensitive to even partial perturbation of the spliceosome.
MYC hyperactivation amplifies RNA transcription, Westbrook added. Mis-splicing leads to neopeptides that act as neoantigens that can stimulate antitumor immune response. Spliceosome-targeted therapies (STTs) can produce mis-spliced RNA to trigger viral mimicry in TNBC cells, inducing gene expression programs that resemble antiviral immune response.
“STTs stimulate robust RNA misprocessing at the global level,” he said. He noted that STTs stimulate tumor cell-intrinsic antiviral pathways that engage downstream adaptive immunity in TNBC.
“There are opportunities that lead to tumor regression and long-term activity,” Westbrook continued. “We need to determine which RBP perturbations best activate antiviral pathways and immune memory, the most effective mediator, and which immune modulators such as checkpoint inhibitors can be combined with STTs to enhance anti-cancer activity.”
Exploiting polyadenylation in tumor immunity
Polyadenylation is also coming into focus as a novel tumor target. Alternative polyadenylation (APA) diversifies cellular transcriptomes and gives rise to dramatic differences in pro- and antitumor cells with the same genetic background, explained Robert Bradley, PhD, the McIlwain Family Endowed Chair in Data Science and Scientific Director of the Translational Data Science Integrated Resource Center at the Fred Hutch Cancer Center.
The Cancer Genome Atlas shows clear correlations between global APA and patient outcomes, he continued. Long 3’ untranslated region (UTR) correlates with worse prognosis in cutaneous melanoma, head and neck squamous cell carcinoma, and low-grade gliomas. Shorter 3’ UTRs correlate with worse prognosis in breast cancer, ovarian cancer, lung adenocarcinoma, and other cancer types.
Knocking out the ATG7 gene in mouse models has been shown to significantly slow melanoma growth and increase survival by altering cell-cycle kinetics, he continued, and researchers have observed that higher ATG7 expression correlates with improved immune checkpoint blockade and increased survival.
“We’re really excited to continue exploring functional roles for APA in cancer,” Bradley said.
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