REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks

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Abstract
Significance: Mutagenic translesion synthesis (TLS) increases cell survival after DNA damage by bypassing lesions that normally block DNA replication but introduces mutations. In cancer cells, REV1/POLζ-dependent mutagenic TLS can contribute to intrinsic chemoresistance, while the mutations it introduces can underlie acquired chemoresistance. Interfering with this TLS pathway genetically or with the small molecule inhibitor JH-RE-06 has been shown to improve cisplatin chemotherapy by suppressing tumor growth and enhancing survival in mouse xenograft tumor models. Cisplatin chemotherapy commonly exerts its antitumor effects via DNA damage-mediated apoptosis. However, in two mouse xenograft models and four mammalian cell lines, the JH-RE-06 unexpectedly profoundly alters the biological response to cisplatin. Apoptosis is suppressed and surprisingly numerous hallmarks of senescence are induced prior to cell death.
Funding Information
  • HHS | NIH | National Institute of Environmental Health Sciences (ES028303)
  • HHS | NIH | National Institute of Environmental Health Sciences (P30 ES002109)
  • HHS | NIH | National Cancer Institute (CA191448)
  • HHS | NIH | National Cancer Institute (CA224144)
  • HHS | NIH | National Cancer Institute (R35CA242379)
  • Duke CTSA (UL1TR002553)
  • Damon Runyon Cancer Research Foundation (DRG-2299-17)
  • Howard Hughes Medical Institute (Faculty scholars award)
  • Ludwig Center at MIT (Support)
  • Alberta Emerald Foundation (Support)
  • Center for Precision Cancer Medicine at MIT (Support)

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