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Autocrine activation of JAK2 by IL-11 promotes platinum drug resistance

Wei Zhou1,2,3, Wei Sun4, Mingo M H Yung5

  • 1Department of Biochemistry and Molecular Medicine, The George Washington University School of Medicine and Health Sciences, Washington, DC, 20037, USA.

Oncogene
|April 18, 2018
PubMed

Insights

Reactive oxygen species (ROS) drive platinum-resistant ovarian cancer by boosting IL-11, which activates JAK2-STAT5. Inhibiting JAK2 or IL-11 resensitizes tumors to platinum drugs, offering new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Platinum-based chemotherapy is a cornerstone in ovarian cancer treatment.
  • Treatment failure due to platinum drug resistance remains a significant clinical challenge.
  • Reactive oxygen species (ROS) are implicated in cancer drug resistance, but the underlying molecular mechanisms are unclear.

Purpose of the Study:

  • To elucidate the molecular link between ROS and cellular survival pathways in platinum-resistant ovarian cancer.
  • To identify novel therapeutic targets for overcoming platinum resistance in ovarian cancer.

Main Methods:

  • Quantitative high-throughput combinational screening (qHTCS) and genomic sequencing were employed.
  • Investigated the role of ROS, IL-11, FRA1, and the JAK2-STAT5 pathway in platinum resistance.
  • Utilized in vitro and in vivo models, along with clinical patient studies.

Main Results:

  • Elevated ROS levels in platinum-resistant ovarian cancer sustain high IL-11 expression via FRA1.
  • Increased IL-11 constitutively activates JAK2-STAT5 through an autocrine mechanism, conferring platinum resistance.
  • Inhibition of JAK2 (LY2784544) or IL-11 (anti-IL-11 antibody) reversed platinum resistance.
  • Activated IL-11-JAK2 pathway was confirmed in patient samples and correlated with poor prognosis.

Conclusions:

  • A novel ROS-IL-11-JAK2-mediated mechanism drives platinum resistance in ovarian cancer.
  • Targeting the IL-11-JAK2 pathway presents a promising therapeutic strategy for platinum-resistant ovarian cancer.
  • LY2784544 or IL-11-targeted immunotherapy offers a new avenue for treating resistant ovarian cancer.

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