Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• RNA-binding motif protein 10 (RBM10) is frequently mutated in lung adenocarcinoma (LUAD), with loss-of-function mutations correlating with increased tumorigenesis.
• Current LUAD targeted therapies are limited by RBM10 mutations, and therapeutic strategies exploiting RBM10 deficiency remain unexplored.

Purpose of the Study:

• To identify therapeutic targets synthetic lethal with RBM10 deficiency in LUAD.
• To elucidate the functional role of RBM10 in DNA replication and replication stress response.

Main Methods:

• CRISPR-Cas9 synthetic lethality (SL) screen to identify RBM10 SL genes.
• In vitro and in vivo studies to assess the efficacy of WEE1 inhibition in RBM10-deficient LUAD cells.
• Mechanistic studies involving DNA replication fork progression, replication stress response, and protein-protein interactions.

Main Results:

• Identified approximately 60 RBM10 SL genes, including WEE1 kinase.
• WEE1 inhibition demonstrated efficacy in sensitizing RBM10-deficient LUAD cells both in vitro and in vivo.
• Uncovered a splicing-independent role of RBM10 in regulating DNA replication fork stability through interaction with PRIM1 and recruitment of HDAC1 for H4K16 deacetylation and R-loop homeostasis.

Conclusions:

• RBM10 plays a critical role in maintaining DNA replication fork stability and replication stress response.
• WEE1 inhibition represents a promising therapeutic strategy for RBM10-deficient LUAD.
• This study provides a new therapeutic avenue for targeting LUAD tumors with RBM10 mutations.