Novel CRISPR-Based Cancer Therapy Offers New Solutions

Exploiting Cancer’s Weakness: Scientists Discover New Synthetic Lethal Target in Tumor Cells

CRISPR-Based cancer therapy. Image provided by Synthego

Last month, a team of researchers at AbbVie discovered SKI and PELO-HBS1L as synthetic lethal targets in certain tumor cells. Both are part of an mRNA quality control pathway, where “phenotypically destabilized SKI complex leads to dependence on the PELO-HBS1L ribosomal rescue complex.” These findings provide auspicious targets for efficient, highly selective cancer treatment, utilizing the CRISPR/Cas system. 

This is a diagram of the mechanism of synthetic lethality. Image provided by Nature Reviews Genetics.

Synthetic lethality, coined with respect to a finding in fruit flies, describes the phenomenon where two non-essential genes are defective simultaneously will lead to cell death. More broadly, is ‘induced essentiality’ or gene addiction, where the genome demonstrates a certain plasticity, allowing it to buffer itself as to survive with certain genetic dysfunctions: various other genetic changes are made to compensate for a major change in a tumor suppressor loss-of-function or oncogene gain-of-function – the cell thus leverages these induced effects for survival. The cell is addicted. 

In this study, targeting mRNA quality control complexes induced abnormal cell cycles by initiating the unfolded protein response (UPR) to a point of lethality. UPR is where the cell attempts to degrade dysfunctional and abnormal proteins, halt translation, and increase chaperoning of protein folding. Ultimately, if the cell remains in a state of dysregulation, UPR will guide the cell towards apoptosis. The specific kind of tumor cells used in this project were ones with 9p21.3 deletions (i.e. mutations on the short arm of chromosome 9, associated with several kinds of cancer, with cell cycle regulation and DNA repair pathways). Accordingly, the 9p21.3 deletions lead to a high dependence on mRNA quality control systems as more faulty mRNA is produced. When both SKI and PELO genes are inhibited, the accumulation of dysfunctional mRNA drives the cell into a lethal form of UPR. 

This vulnerability of cancer cells can be and has been exploited. A classic example of non-paralogue synthetic lethal relationships in cancer is PARP1-PARP2 DNA repair enzymes (homologous recombination) and BRCA1-BRCA2 tumor suppressor genes. However, the novel targets postulated in this paper are not as well understood; its causal mechanism remains opaque. The team indicates that more robust proteomic data is required to characterize and extrapolate this relationship “across all cancer cell line models.”

Nevertheless, the discovery of this new synthetically lethal target is both exciting and auspicious. Targeted therapy boasts higher precision towards cancer cells and reduced side effects (in the PARP inhibitor model) than traditional chemotherapy. Exploiting the cell’s unique vulnerabilities can mark a new era in precision oncology, offering cancer patients more effective and less toxic therapeutic options.