Irreversible JNK blockade overcomes PD-L1-mediated resistance to chemotherapy in colorectal cancer

Lei Sun, Árpád V. Patai, Tara L. Hogenson, Martin E. Fernandez-Zapico, Bo Qin, Frank A. Sinicrope

Research output: Contribution to journalArticlepeer-review


Colorectal cancer (CRC) cells have low or absent tumor cell PD-L1 expression that we previously demonstrated can confer chemotherapy resistance. Here, we demonstrate that PD-L1 depletion enhances JNK activity resulting in increased BimThr116 phosphorylation and its sequestration by MCL-1 and BCL-2. Activated JNK signaling in PD-L1-depeted cells was due to reduced mRNA stability of the CYLD deubiquitinase. PD-L1 was found to compete with the ribonuclease EXOSC10 for binding to CYLD mRNA. Thus, loss of PD-L1 promoted binding and degradation of CYLD mRNA by EXOSC10 which enhanced JNK activity. An irreversible JNK inhibitor (JNK-IN-8) reduced BimThr116 phosphorylation and unsequestered Bim from MCL-1 and BCL-2 to promote apoptosis. In cells lacking PD-L1, treatment with JNK-IN-8, an MCL-1 antagonist (AZD5991), or their combination promoted apoptosis and reduced long-term clonogenic survival by anticancer drugs. Similar effects of the JNK inhibitor on cell viability were observed in CRC organoids with suppression of PD-L1. These data indicate that JNK inhibition may represent a promising strategy to overcome drug resistance in CRC cells with low or absent PD-L1 expression.

Original languageEnglish (US)
Pages (from-to)5105-5115
Number of pages11
Issue number32
StatePublished - Aug 12 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research


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