Related Experiment Video

Updated: Sep 11, 2025

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

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Assessing Determinants of Response to PARP Inhibition in Germline ATM Mutant Melanoma

Eleonora Allavena1,2, Michela Croce3, Bruna Dalmasso2

  • 1Department of Internal Medicine and Medical Specialties, University of Genoa, 16132 Genoa, Italy.

International Journal of Molecular Sciences
|August 14, 2025
PubMed

Insights

Deleterious ATM variants and homologous recombination deficiency (HRD) did not predict PARP inhibitor (PARPi) sensitivity in melanoma. SLFN11 silencing contributed to resistance, suggesting comprehensive approaches are needed for effective melanoma treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • The ataxia-telangiectasia-mutated (ATM) protein is vital for DNA damage response and homologous recombination (HR).
  • ATM variants can lead to homologous recombination deficiency (HRD), a target for PARP inhibitors (PARPi).
  • Melanoma treatment efficacy can vary, necessitating a deeper understanding of resistance mechanisms.

Purpose of the Study:

  • To investigate the impact of germline ATM variants on HRD and PARPi response in melanoma.
  • To explore the role of SLFN11 expression in PARPi resistance in ATM-mutant melanoma.
  • To evaluate the potential of combining ATR inhibitors (ATRi) with PARPi.

Main Methods:

  • Established a melanoma cell line from a patient with a germline ATM variant (c.5979_5983del).
  • Assessed HRD, ATM activation, SLFN11 expression, and promoter methylation.
  • Tested sensitivity to PARPi, ATRi, and combination therapy.

Main Results:

  • The ATM-mutant cell line exhibited HRD but lacked sensitivity to PARPi.
  • SLFN11 expression was absent due to hypermethylation-mediated promoter silencing.
  • While sensitive to ATRi, the combination of ATRi and PARPi did not overcome PARPi resistance.

Conclusions:

  • ATM mutational status and HRD alone are insufficient to predict PARPi response in this melanoma model.
  • SLFN11 silencing is a potential mechanism of PARPi resistance.
  • A multifaceted strategy is required to optimize DNA repair defect-targeted therapies for melanoma patients.
Keywords:
ATMHRDPARPigermline variationmelanoma

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