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Cooperation of the ATM and Fanconi Anemia/BRCA Pathways in Double-Strand Break End Resection

Mu-Yan Cai1, Connor E Dunn2, Wenxu Chen1

  • 1Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.

Cell Reports
|February 21, 2020
PubMed

Insights

Lung cancer cells with defects in the Fanconi anemia/BRCA pathway are sensitive to ATM inhibitors. Combining ATM inhibition with FA/BRCA pathway defects causes synthetic lethality, offering a potential cancer therapy strategy.

Area of Science:

  • Genetics
  • Cancer Biology
  • Molecular Oncology

Background:

  • Ataxia telangiectasia mutated (ATM) deficient cells exhibit hypersensitivity to DNA damaging agents.
  • ATM inhibitors are being explored to sensitize cancer cells to anti-cancer therapies.
  • Identifying genetic vulnerabilities can predict response to ATM inhibitor monotherapy.

Purpose of the Study:

  • To identify genetic vulnerabilities sensitizing lung cancer cells to ATM inhibitors using a genome-wide CRISPR screen.
  • To elucidate the mechanism of synthetic lethality induced by ATM inhibitors in combination with DNA repair pathway defects.

Main Methods:

  • Genome-wide CRISPR screen in lung cancer cells.
  • Treatment with ATM inhibitor M3541.
  • Assessment of DNA double-strand break repair pathways (homologous recombination and non-homologous end joining).

Main Results:

  • Knockout of Fanconi anemia (FA)/BRCA pathway genes conferred hypersensitivity to the ATM inhibitor M3541.
  • Combined deficiency in FA/BRCA pathway and ATM led to reduced DNA end resection and enhanced non-homologous end joining (NHEJ).
  • This combination resulted in toxic levels of NHEJ, causing synthetic lethality.

Conclusions:

  • Defects in the FA/BRCA pathway sensitize cancer cells to ATM inhibitors.
  • ATM inhibitors may be effective as monotherapy for tumors with a defective FA/BRCA pathway.
  • Synthetic lethality through combined targeting of ATM and FA/BRCA pathway offers a novel therapeutic strategy.
Keywords:
ATM inhibitorCRISPR sgRNA screeningFanconi anemia pathwayNHEJend resection

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