Cancers (Basel). 2021 Dec 15. pii: 6295. [Epub ahead of print]13(24):
Ymera Pignochino,
Giovanni Crisafulli,
Giorgia Giordano,
Alessandra Merlini,
Enrico Berrino,
Maria Laura Centomo,
Giulia Chiabotto,
Silvia Brusco,
Marco Basiricò,
Elena Maldi,
Alberto Pisacane,
Valeria Leuci,
Dario Sangiolo,
Lorenzo D'Ambrosio,
Massimo Aglietta,
Bernd Kasper,
Alberto Bardelli,
Giovanni Grignani.
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.
Keywords: DNA damage response and repair genes; advanced sarcomas; mutational signatures; olaparib; trabectedin; tumor mutational burden