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JAK2 Inhibitor SAR302503 Abrogates PD-L1 Expression and Targets Therapy-Resistant Non-small Cell Lung Cancers

Sean P Pitroda1, Melinda E Stack2, Gene-Fu Liu1

  • 1Department of Radiation and Cellular Oncology and Ludwig Center for Metastasis Research, The University of Chicago, Chicago, Illinois.

Molecular Cancer Therapeutics
|February 23, 2018
PubMed

Insights

This study shows SAR302503 (SAR), a JAK2 inhibitor, effectively kills non-small cell lung cancer (NSCLC) cells resistant to standard therapies. SAR may offer new treatment options for NSCLC patients, potentially combined with immunotherapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Non-small cell lung cancer (NSCLC) remains a leading cause of cancer mortality worldwide.
  • Current NSCLC treatments targeting oncogenes and immune checkpoints have limited long-term survival rates.
  • Developing novel therapeutic strategies for resistant NSCLC is critical.

Purpose of the Study:

  • To investigate the efficacy of SAR302503 (SAR), a selective JAK2 inhibitor, in NSCLC.
  • To determine if SAR overcomes resistance to genotoxic therapies in NSCLC.
  • To explore the role of interferon-stimulated genes and PD-L1 in SAR response.

Main Methods:

  • Treatment of NSCLC cell lines and tumors with SAR302503.
  • Assessment of cytotoxicity and resistance to genotoxic agents (ionizing radiation, cisplatin, etoposide).
  • Analysis of interferon-stimulated gene expression and PD-L1 levels.

Main Results:

  • SAR demonstrated cytotoxicity against NSCLC cells, including those resistant to genotoxic therapies.
  • Constitutive interferon-stimulated gene expression predicted sensitivity to SAR.
  • SAR abrogated tumor cell-intrinsic, interferon-inducible PD-L1 expression.

Conclusions:

  • JAK2 inhibitors like SAR may serve as a novel monotherapy for NSCLC resistant to genotoxic treatments.
  • SAR holds potential for combination therapy with immune checkpoint inhibitors.
  • Understanding IFN-stimulated genes and PD-L1 regulation is key for JAK2 inhibitor efficacy in NSCLC.

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