JAK-STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression

Int J Cancer. 2019 Dec 15;145(12):3376-3388. doi: 10.1002/ijc.32624. Epub 2019 Sep 10.

Abstract

Oncogenic K-RAS has been difficult to target and currently there is no K-RAS-based targeted therapy available for patients suffering from K-RAS-driven lung adenocarcinoma (AC). Alternatively, targeting K-RAS-downstream effectors, K-RAS-cooperating signaling pathways or cancer hallmarks, such as tumor-promoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAK-STAT pathway is considered to be a central player in inflammation-mediated tumorigenesis, we investigated here the implication of JAK-STAT signaling and the therapeutic potential of JAK1/2 inhibition in K-RAS-driven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAK-STAT signaling correlated with disease progression and K-RAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of K-RAS-driven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumor-promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K-RAS-driven lung AC.

Keywords: Janus kinase (JAK); Kirsten rat sarcoma viral proto-oncogene (K-RAS); cell-line derived xenografts; genetically engineered mouse models; lung adenocarcinoma (AC); non-small cell lung cancer; ruxolitinib; tumor microenvironment (TME); tumor promoting inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • Adenocarcinoma of Lung / drug therapy*
  • Adenocarcinoma of Lung / metabolism
  • Adenocarcinoma of Lung / pathology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Disease Progression
  • Humans
  • Janus Kinase Inhibitors / pharmacology*
  • Janus Kinases / antagonists & inhibitors*
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Mice, SCID
  • Proto-Oncogene Proteins p21(ras) / metabolism*
  • STAT Transcription Factors / antagonists & inhibitors*
  • Signal Transduction / drug effects
  • Tumor Microenvironment / drug effects

Substances

  • Antineoplastic Agents
  • Janus Kinase Inhibitors
  • KRAS protein, human
  • STAT Transcription Factors
  • Janus Kinases
  • Proto-Oncogene Proteins p21(ras)