Assessing Determinants of Response to PARP Inhibition in Germline ATM Mutant Melanoma
The ataxia-telangiectasia-mutated (ATM) protein plays a crucial role in the DNA damage response, particularly in the homologous recombination (HR) pathway. This study aimed to assess the impact of deleterious <i>ATM</i> variants on homologous recombination deficiency (HRD) and response to PARP inhibitors (PARPi) in melanoma patients, using a cell line established from melanoma tissue of a patient carrying the c.5979_5983del germline <i>ATM</i> variant. Despite proven loss of heterozygosity, lack of ATM activation, and HRD, our model did not show sensitivity to PARPi. We assessed the potential contribution of the Schlafen family member 11 (SLFN11) helicase, whose expression is inversely correlated with PARPi sensitivity in other cancers, to the observed resistance. The ATM mutant cell line lacked SLFN11 expression and featured hypermethylation-mediated silencing of the SLFN11 promoter. While sensitive to the ATR inhibitor (ATRi), the addition of ATRi to PARPi was unable to overcome the resistance. Our findings suggest that <i>ATM</i> mutational status and HRD alone do not adequately account for variations in sensitivity to PARPi in our model. A comprehensive approach is essential for optimizing the exploitation of DNA repair defects and ultimately improving clinical outcomes for melanoma patients.
Authors
- Benedetta Pellegrino (ORCID: https://orcid.org/0000-0001-9353-7445)
- Enrica T. Tanda (ORCID: https://orcid.org/0000-0002-1552-9826)
- Irene Vanni (ORCID: https://orcid.org/0000-0001-5900-4880)
- Lorenza Pastorino (ORCID: https://orcid.org/0000-0002-2575-8331)
- E. Allavena
- Paola Ghiorzo (ORCID: https://orcid.org/0000-0002-3651-8173)
- William Bruno (ORCID: https://orcid.org/0000-0002-0337-0168)
- Bruna Dalmasso (ORCID: https://orcid.org/0000-0002-1534-0521)
- Francesco Spagnolo (ORCID: https://orcid.org/0000-0003-3287-1225)
- Luca Mastracci (ORCID: https://orcid.org/0000-0003-0193-5281)
- Antonino Musolino (ORCID: https://orcid.org/0000-0002-7979-6261)
- Gabriele Zoppoli (ORCID: https://orcid.org/0000-0002-1619-1708)
- Nicoletta Campanini (ORCID: https://orcid.org/0009-0006-7259-5869)
- Virginia Andreotti (ORCID: https://orcid.org/0000-0002-2569-0832)
- Michela Croce (ORCID: https://orcid.org/0000-0003-4683-4951)
- Valentina Rigo (ORCID: https://orcid.org/0000-0002-2032-3929)
- Cecilia Profumo (ORCID: https://orcid.org/0009-0004-8962-6487)
Institutions
- University of Parma (IT)
- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IT)
- Ospedale Policlinico San Martino (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- University of Genoa (IT)
- University of Bologna (IT)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-08-01
- DOI
- https://doi.org/10.3390/ijms26157420
- Citations
- 1
- Primary Topic
- PARP inhibition in cancer therapy
- Type
- article
- Field-Weighted Citation Impact
- 1.05
Funders
- Ministero della Salute
- Alleanza Contro il Cancro