Open AccessCatastrophic ATP loss underlies a metabolic combination therapy tailored for MYCN -amplified neuroblastoma
Author(s) -
Krista M. Dalton,
Timothy L. Lochmann,
Konstantinos V. Floros,
Marissa L. Calbert,
Richard Kurupi,
Giovanna T. Stein,
Joseph McClanaghan,
Ellen Murchie,
Regina K. Egan,
Patricia Greninger,
Mikhail G. Dozmorov,
Sivapriya Ramamoorthy,
Madhavi Puchalapalli,
Bin Hu,
Lisa S. Shock,
Jennifer E. Koblinski,
John Glod,
Sosipatros A. Boikos,
Cyril H. Benes,
Anthony C. Faber
Publication year - 2021
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2009620118
Subject(s) - neuroblastoma , pediatric cancer , cancer research , biology , combination therapy , synthetic lethality , cancer , pharmacology , genetics , dna repair , gene , cell culture
Significance High-risk neuroblastoma accounts for nearly 15% of all pediatric cancer-related deaths. MYCN is an oncogene amplified in roughly half of high-risk neuroblastoma cases and finding new therapies to neutralize MYCN is a high priority for pediatric cancer. Here we demonstrate thatMYCN -amplified neuroblastomas are sensitive to the combined inhibition of MCT1 and complex I of the mitochondrion. Sensitivity is due to low expression of MCT4 and high expression of MCT1 and the MCT1 chaperone CD147. Pharmacologic inhibition with AZD3965 and phenformin leads to complementary inhibition of metabolic processes that ultimately leads to cell death.
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