Deciphering the nonsense-mediated mRNA decay pathway to identify cancer cell vulnerabilities for effective cancer therapy

Abstract

Nonsense-mediated mRNA decay (NMD) is a highly conserved cellular surveillance mechanism, commonly studied for its role in mRNA quality control because of its capacity of degrading mutated mRNAs that would produce truncated proteins. However, recent studies have proven that NMD hides more complex tasks involved in a plethora of cellular activities. Indeed, it can control the stability of mutated as well as non-mutated transcripts, tuning transcriptome regulation. NMD not only displays a pivotal role in cell physiology but also in a number of genetic diseases. In cancer, the activity of this pathway is extremely complex and it is endowed with both pro-tumor and tumor suppressor functions, likely depending on the genetic context and tumor microenvironment. NMD inhibition has been tested in pre-clinical studies showing favored production of neoantigens by cancer cells, which can stimulate the triggering of an anti-tumor immune response. At the same time, NMD inhibition could result in a pro-tumor effect, increasing cancer cell adaptation to stress. Since several NMD inhibitors are already available in the clinic to treat genetic diseases, these compounds could be redirected to treat cancer patients, pending the comprehension of these variegated NMD regulation mechanisms. Ideally, an effective strategy should exploit the anti-tumor advantages of NMD inhibition and simultaneously preserve its intrinsic tumor suppressor functions. The targeting of NMD could provide a new therapeutic opportunity, increasing the immunogenicity of tumors and potentially boosting the efficacy of the immunotherapy agents now available for cancer treatment.

Keywords: Combination therapy; Immune checkpoint inhibitors; Neoantigens; Nonsense mutations.

Fig. 1

Pro- and anti-tumor effects of NMD inhibition. NMD has been shown to play a critical role in tumors, displaying, at the same time, a pro-tumor and tumor suppressor activity, depending on the genetic context and tumor microenvironment. NMD, degrading mRNAs with a PTC, protects cells from the formation of potentially toxic proteins. Indeed NMD pathway inhibition results in tumor cell toxicity due to the accumulation of mutated protein. Moreover, immunogenic peptides, derived from these proteins, could act as neoantigens able to activate T-cell response against tumor cells, inducing so an immune-dependent reduction of tumor growth. Furthermore, NMD physiologically regulates genes involved in DNA damage response, so NMD inhibition results in a reduction of tumor capacity to respond to DNA damage and in a greater sensitivity to chemotherapy. On the other hand, for its tumor-suppressor role, NMD is often inhibited by microenvironmental cues, as hypoxia or oxidative stress, determining an increased expression of ISR components, like ATF3 and CHOP, or antioxidant agent such as SLC7A11. In this way, NMD inhibition protects cancer cells from elevated level of ROS and reduced oxygen concentration allowing tumor adaptation to stress conditions. Moreover, impaired NMD was found to favor activation of the NF-kB pathway so inducing an inflammatory state and favoring tumor cell survival. Adapted from BioRender.com