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Harnessing DNA replication stress to target RBM10 deficiency in lung adenocarcinoma

Feras E Machour1, Enas R Abu-Zhayia1, Joyce Kamar2

  • 1Department of Biology, Technion-Israel Institute of Technology, Haifa, Israel.

Nature Communications
|July 30, 2024
PubMed

Insights

Targeting RNA-binding motif protein 10 (RBM10) deficiency in lung adenocarcinoma (LUAD) is a novel therapeutic strategy. Inhibiting WEE1 kinase exploits RBM10 loss-of-function, offering new treatment options for LUAD patients.

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.

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