Passenger deletions generate therapeutic vulnerabilities in cancer.
Inactivation of tumour-suppressor genes by homozygous deletion is a prototypic event in the cancer genome, yet such deletions often encompass neighbouring genes. We propose that homozygous deletions in such passenger genes can expose cancer-specific therapeutic vulnerabilities when the collaterally deleted gene is a member of a functionally redundant family of genes carrying out an essential function. The glycolytic gene enolase 1 (ENO1) in the 1p36 locus is deleted in glioblastoma (GBM), which is tolerated by the expression of ENO2. Here we show that short-hairpin-RNA-mediated silencing of ENO2 selectively inhibits growth, survival and the tumorigenic potential of ENO1-deleted GBM cells, and that the enolase inhibitor phosphonoacetohydroxamate is selectively toxic to ENO1-deleted GBM cells relative to ENO1-intact GBM cells or normal astrocytes. The principle of collateral vulnerability should be applicable to other passenger-deleted genes encoding functionally redundant essential activities and provide an effective treatment strategy for cancers containing such genomic events.
Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Florian L
FL
Muller
Simona
S
Colla
Elisa
E
Aquilanti
Veronica E
VE
Manzo
Giannicola
G
Genovese
Jaclyn
J
Lee
Daniel
D
Eisenson
Rujuta
R
Narurkar
Pingna
P
Deng
Luigi
L
Nezi
Michelle A
MA
Lee
Baoli
B
Hu
Jian
J
Hu
Ergun
E
Sahin
Derrick
D
Ong
Eliot
E
Fletcher-Sananikone
Dennis
D
Ho
Lawrence
L
Kwong
Cameron
C
Brennan
Y Alan
YA
Wang
Lynda
L
Chin
Ronald A
RA
DePinho
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000172:deficiency / Q000235:genetics; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D004791:Enzyme Inhibitors; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D020043:Genes, Essential / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D006720:Homozygote; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D009368:Neoplasm Transplantation; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D010751:Phosphopyruvate Hydratase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C087412:phosphonoacetohydroxamate; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase; D010746:Phosphonoacetic Acid