Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy.
ONYX-015 is an E1B-55K-deleted adenovirus that has promising clinical activity as a cancer therapy. However, many tumor cells fail to support ONYX-015 oncolytic replication. E1B-55K functions include p53 degradation, RNA export, and host protein shutoff. Here, we show that resistant tumor cell lines fail to provide the RNA export functions of E1B-55K necessary for ONYX-015 replication; viral 100K mRNA export is necessary for host protein shutoff. However, heat shock rescues late viral RNA export and renders refractory tumor cells permissive to ONYX-015. These data indicate that heat shock and late adenoviral RNAs may converge upon a common mechanism for their export. Moreover, these data suggest that the concomitant induction of a heat shock response could significantly improve ONYX-015 cancer therapy.
O'Shea
Clodagh C
CC
Cancer Research Institute, University of California, San Francisco, CA 94115, USA. coshea@cc.ucsf.edu
Soria
Conrado
C
Bagus
Bridget
B
McCormick
Frank
F
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017501:Adenovirus E1B Proteins / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006358:Hot Temperature / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D010641:Phenotype; D034443:RNA Transport; D012367:RNA, Viral / Q000378:metabolism; D012769:Shock / Q000628:therapy; D017361:Viral Nonstructural Proteins / Q000378:metabolism; D014765:Viral Vaccines; D014779:Virus Replication / Q000235:genetics
D017501:Adenovirus E1B Proteins; D000970:Antineoplastic Agents; C477284:L4-100K protein, adenovirus type 5; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D014765:Viral Vaccines; C464532:dl1520