Cancer-associated FBXW7 Loss is Synthetic Lethal with Pharmacological Targeting of CDC7

Overview

Journal Mol Oncol

Specialties Molecular Biology
Oncology

Date 2023 Oct 22

PMID 37866880

Authors

Joseph S Baxter

Rachel Brough

Dragomir B Krastev

Feifei Song

Sandhya Sridhar

Aditi Gulati

John Alexander

Theodoros I Roumeliotis

Zuza Kozik

Jyoti S Choudhary

Syed Haider

Stephen J Pettitt

Andrew N J Tutt

Christopher J Lord

Affiliations

Soon will be listed here.

Abstract

The F-box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate-recognition subunit of Skp, cullin, F-box (SCF)-containing complexes. The tumour-suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens, focussed RNA-interference screens and whole and phospho-proteome mass spectrometry profiling in multiple FBXW7 wild-type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7-related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small-molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere-associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7-selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.

Citing Articles

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Synthetic lethal strategies for the development of cancer therapeutics.

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