Blocking splicing pathway suppresses aggressive cancer growth

Reducing the activity of a single protein by half can significantly suppress tumour growth across multiple cancer types, according to new research.

KRAS is a gene involved in signalling pathways that control how cells grow, mature and die. When mutations affect its functioning, they can lead to cell proliferation: KRAS mutations are found in about 25 percent of all cancers (see BioNews 1189), and are also seen in endometriosis (see BioNews 900). Researchers at the Walter and Eliza Hall Institute (WEHI) in Melbourne, Australia, found that halving levels of a protein called RNPC3 can significantly suppress tumour growth in KRAS-driven cancers, without damaging healthy cells.

'KRAS mutations come in a variety of flavours, making them extremely hard to treat,' said Professor Joan Heath, who led the study published in EMBO Reports. 'Instead of trying to target specific mutations... we're disrupting a fundamental process that these fast-growing cancers rely on.'

Targeted drugs – such as sotorasib and adagrasib – have been developed to treat tumours with specific KRAS mutations, but most patients eventually develop resistance.

The RNPC3 approach sidesteps mutation-specific targeting. Professor Heath and her colleagues showed that RNPC3 reduction disrupts a specialised part of RNA processing called minor splicing. This triggered DNA damage and activated tumour-suppressor responses, causing cancer cells to die.

Although minor splicing affects only around 700 genes – 0.35 percent of the genome – these genes are essential for cell division. Cancer cells, which divide rapidly, rely heavily on them, and targeting RNPC3 exploits this vulnerability.

The WEHI team tested the strategy across zebrafish, mouse and human cancer models, demonstrating consistent tumour suppression. To bring this approach closer to the clinic, the researchers are now looking to identify drug candidates that inhibit RNPC3.

Previous clinical trials for cancer therapies that target splicing machinery have been unsuccessful due to side effects or insufficient difference between effects on cancer and healthy cells. However, RNPC3 inhibition avoids blanket suppression of splicing machinery. It targets a part that appears to matter more to cancer cells than to healthy ones – potentially reducing the risk of side effects.

'This opens the door to treatments that could be both more effective and less toxic, offering hope for patients with aggressive cancers that currently have limited options,' said the study's first author, Dr Karen Doggett.