Year: 2024
Type: article
Abstract: DNA damage resistance is a major barrier to effective DNA-damaging therapy in multiple myeloma (MM). To discover novel mechanisms through which MM cells overcome DNA damage, we investigated how MM cells become resistant to antisense oligonucleotide (ASO) therapy targeting ILF2, a DNA damage regulator that is overexpressed in 70% of MM patients whose disease has progressed after standard therapies have failed. Here, we show that MM cells undergo an adaptive metabolic rewiring and rely on oxidative phosphorylation to restore energy balance and promote survival in response to DNA damage activation. Using a CRISPR/Cas9 screening strategy, we identified the mitochondrial DNA repair protein DNA2, whose loss of function suppresses MM cells' ability to overcome ILF2 ASO-induced DNA damage, as being essential to counteracting oxidative DNA damage and maintaining mitochondrial respiration. Our study revealed a novel vulnerability of MM cells that have an increased demand for mitochondrial metabolism upon DNA damage activation. STATEMENT OF SIGNIFICANCE: Metabolic reprogramming is a mechanism through which cancer cells maintain survival and become resistant to DNA-damaging therapy. Here, we show that targeting DNA2 is synthetically lethal in myeloma cells that undergo metabolic adaptation and rely on oxidative phosphorylation to maintain survival after DNA damage activation.
Source: Nature Communications
Authors: Natthakan Thongon, Feiyang Ma, Natalia Baran, Pamela Lockyer, Jintan Liu, Christopher Jackson, Ashley Rose, Ken Furudate, Bethany Wildeman, Matteo Marchesini, Valentina Marchica, Paola Storti, Giannalisa Todaro, Irene Ganan-Gomez, Vera Adema, Juan Jose Rodriguez-Sevilla, Yun Qing, Min Jin Ha, Rodrigo Fonseca, Caleb Stein, Caleb Class, Lin Tan, Sergio Attanasio, Guillermo Garcia-Manero, Nicola Giuliani, David Berrios Nolasco, Andrea Santoni, Claudio Cerchione, Carlos Bueso-Ramos, Marina Konopleva, Philip Lorenzi, Koichi Takahashi, Elisabet Manasanch, Gabriella Sammarelli, Rashmi Kanagal-Shamanna, Andrea Viale, Marta Chesi, Simona Colla
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,790
Awards: G132965223, SPORE University of Texas M. D. Anderson Cancer Center-Leukemia, G1619438925, G1727840030, G1915563957, G2253147395, G2383814189, G2390440901, G2541397611, G4822627030, Validation of Critical 1q21 Vulnerabilities in Multiple Myeloma, G5635995581, G640481018, Credentialing a Genetically Engineered Clinically-Relevant Mouse Model of Multiple Myeloma, G9000037087, Cancer Center Support Grant, Mayo Clinic Multiple Myeloma SPORE, preclinical optimization of BCMA directed T cell therapy, Dana-Farber/Harvard Cancer Center
OpenAlex ID: W4391643184