CRISPR metabolic screen identifies ATM and KEAP1 as targetable genetic vulnerabilities in solid tumors

Area of Science:

• Molecular Oncology
• Cancer Metabolism
• DNA Damage Response

Background:

• Cancer treatments targeting DNA repair deficiencies often face drug resistance.
• Alternative metabolic pathways may contribute to resistance by counteracting DNA damage effects.
• The DNA damage response kinase Ataxia-telangiectasia-mutated (ATM) is a key target in cancer therapy.

Purpose of the Study:

• To identify metabolic pathways that exhibit synthetic lethality with ATM inhibition.
• To investigate the role of Kelch-like ECH-associated protein 1 (KEAP1) in resistance to ATM inhibition.

Main Methods:

• Screened for metabolic pathways synthetic lethal with ATM inhibition using a CRISPR/Cas9 library.
• Assessed the effect of KEAP1 depletion on cancer cell sensitivity to ATM inhibition in vitro and in vivo.
• Analyzed The Cancer Genome Atlas (TCGA) pan-cancer datasets for correlations between ATM and KEAP1 levels.

Main Results:

• KEAP1 was identified as a key factor desensitizing cancer cells to ATM inhibition.
• KEAP1-depleted cells overexpressed SLC7A11, accumulated cystine, and showed increased disulfide stress, leading to hypersensitivity to ATM inhibition.
• ATM levels negatively correlated with KEAP1 levels across multiple solid tumors in TCGA datasets.

Conclusions:

• Disulfide stress, induced by KEAP1 depletion and SLC7A11 overexpression, is crucial for sensitizing cancer cells to ATM inhibition.
• ATM and KEAP1 represent novel, targetable vulnerabilities in solid tumors.
• Targeting the interplay between DNA damage response and cellular metabolism offers new therapeutic strategies.