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- Title
PARP1 Inhibitor and Trabectedin Combination Does Not Increase Tumor Mutational Burden in Advanced Sarcomas—A Preclinical and Translational Study.
- Authors
Pignochino, Ymera; Crisafulli, Giovanni; Giordano, Giorgia; Merlini, Alessandra; Berrino, Enrico; Centomo, Maria Laura; Chiabotto, Giulia; Brusco, Silvia; Basiricò, Marco; Maldi, Elena; Pisacane, Alberto; Leuci, Valeria; Sangiolo, Dario; D'Ambrosio, Lorenzo; Aglietta, Massimo; Kasper, Bernd; Bardelli, Alberto; Grignani, Giovanni
- Abstract
Simple Summary: Immunotherapy has revolutionized cancer treatment, but not for all tumor types. Indeed, sarcomas are considered "immune-cold" tumors, which are relatively unresponsive to immunotherapy. One strategy to potentiate immunotherapy efficacy is to increase tumor immunogenicity, for instance by boosting the number of candidate targets (neoantigens) to be recognized by the immune system. Tumor mutational burden indicates the number of somatic mutations identified in the tumor and normalized per megabase. Tumor mutational burden is considered as an acceptable, measurable surrogate of tumor neoantigens. Here, we explored whether the combination of two DNA-damaging agents, trabectedin and olaparib, could increase tumor mutational burden in sarcomas, to prime subsequent immunotherapy. We found no variation in tumor mutational burden after trabectedin + olaparib in preclinical and clinical samples. Therefore, other aspects should be considered to increase sarcoma immunogenicity, by exploiting different pathways such as the potential modulation of the tumor microenvironment induced by trabectedin + olaparib. Drug-induced tumor mutational burden (TMB) may contribute to unleashing the immune response in relatively "immune-cold" tumors, such as sarcomas. We previously showed that PARP1 inhibition perpetuates the DNA damage induced by the chemotherapeutic agent trabectedin in both preclinical models and sarcoma patients. In the present work, we explored acquired genetic changes in DNA repair genes, mutational signatures, and TMB in a translational platform composed of cell lines, xenografts, and tumor samples from patients treated with trabectedin and olaparib combination, compared to cells treated with temozolomide, an alkylating agent that induces hypermutation. Whole-exome and targeted panel sequencing data analyses revealed that three cycles of trabectedin and olaparib combination neither affected the mutational profiles, DNA repair gene status, or copy number alterations, nor increased TMB both in homologous recombinant-defective and proficient cells or in xenografts. Moreover, TMB was not increased in tumor specimens derived from trabectedin- and olaparib-treated patients (5–6 cycles) when compared to pre-treatment biopsies. Conversely, repeated treatments with temozolomide induced a massive TMB increase in the SJSA-1 osteosarcoma model. In conclusion, a trabectedin and olaparib combination did not show mutagenic effects and is unlikely to prime subsequent immune-therapeutic interventions based on TMB increase. On the other hand, these findings are reassuring in the increasing warning of treatment-induced hematologic malignancies correlated to PARP1 inhibitor use.
- Subjects
THERAPEUTIC use of antineoplastic agents; GENETIC mutation; XENOGRAFTS; CONFIDENCE intervals; CANCER patients; DESCRIPTIVE statistics; TRANSLATIONAL research; CELL lines; DATA analysis software; ODDS ratio; ENZYME inhibitors; SARCOMA
- Publication
Cancers, 2021, Vol 13, Issue 24, p6295
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13246295