Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma
Background and Motivation: Lung cancer has the highest mortality rate among all types of cancer worldwide. Strikingly, the RNA-binding motif protein 10 (RBM10) is the most mutated splicing factor in lung adenocarcinoma (LUAD) (~9-25% of all cases). Most RBM10 cancer mutations are loss-of-function, correlating with increased tumorigenesis and limiting the efficacy of current LUAD targeted therapies. Remarkably, therapeutic strategies leveraging RBM10 deficiency remain unexplored, highlighting the urgency for innovative approaches to target RBM10 loss in LUAD.
Research Goal: Exploit the high mutation rate of RBM10 in LUAD for selective eradication of RBM10-mutated LUAD tumors.
Results: We conducted a CRISPR-Cas9 synthetic lethality (SL) screen and identified ~60 RBM10 SL genes, including WEE1 kinase. WEE1 inhibition sensitized RBM10-deficient LUAD cells in-vitro and in-vivo. Intriguingly, we identified a splicing-independent role of RBM10 in regulating DNA replication fork progression and replication stress response, which underpins RBM10-WEE1 SL. Mechanistically, we reveal that RBM10 physically interacts with active DNA replication forks and modulates R-loop homeostasis to maintain replication fork stability.
Conclusions: Our data reveal an unexpected function of RBM10 in fine-tuning DNA replication, independent of its canonical splicing function. In a broader context, these findings reveal an unexplored aspect of DNA replication regulation involving a noncanonical function of RNA splicing factors. Moreover, our data provide an arsenal of therapeutic targets, such as WEE1, that can be utilized to target RBM10-mutated LUAD tumors with immediate clinical applicability.
