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Fig. 4 | Molecular Cancer

Fig. 4

From: Nonsense-mediated RNA decay and its bipolar function in cancer

Fig. 4

Summary of nonsense-mediated mRNA decay (NMD) inhibition/escaping and activation strategies for cancer treatment. a NMD activation in cancer therapy. The search of small molecules boosting NMD activity is still under research, but supposes a potential treatment for those cancer types where tumor-suppressive functions of NMD are beneficial. A more developed and gene-specific approach is the use of oligonucleotides designed to promote NMD over cancer- and/or stress-related transcripts. b Global and gene-specific NMD inhibition in cancer therapy. Nonsense suppressor compounds inducing read-through of premature termination codons (PTCs) by the ribosome allow the synthesis of full-length tumor suppressor proteins. This approach can be combined with global NMD inhibition to increase steady-state PTC-containing transcript levels by the use of translational inhibitors, small inhibiting molecules, calcium release modulators or cytoskeleton disrupting agents. In order to avoid non-desired off-targets affected by the general NMD inhibition, antisense oligonucleotides (ASOs) blocking the deposition of an EJC downstream of a PTC allows gene-specific targeting. EJC: exon junction complex. c Global NMD inhibition in cancer immunotherapy. Immune checkpoint inhibitors against negative regulators of T cell activation like CTLA-4 or PD-1 are commonly used in cancer immunotherapy to boost the anti-tumor immune response. NMD inhibition is a potential adjuvant therapy given the propensity of the tumor to produce neoantigens that trigger the immune response. Cancer cells experience numerous frameshift mutations resulting in PTC-containing transcripts that upon NMD inhibition can give rise to neoantigenic peptides detected by the immune system. Moreover, the tumor cellular landscape of NMD-escaping frameshifted transcripts can be used as a biomarker of value for personalized immunotherapy design and prediction of its response

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