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Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC

Gillian Moore1,2, Clara Lightner1, Samira Elbai1

  • 1Department of Clinical Medicine, Trinity Translational Medicine Institute, St. James's Hospital, Dublin, Ireland.

Cancers
|May 5, 2021
PubMed

Insights

This study shows PIM kinase is a poor prognostic marker in non-small cell lung cancer (NSCLC). A novel inhibitor (IBL-301) targeting PI3K/mTOR/PIM kinases effectively reduced cancer cell growth and inflammation in NSCLC models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • PIM kinases are proto-oncogenic serine/threonine kinases involved in cell cycle, metabolism, inflammation, and drug resistance.
  • PIM kinases stabilize key proteins like p53 and c-Myc and interact with the PI3K/Akt pathway.
  • Non-small cell lung cancer (NSCLC) exhibits PIM kinase expression, with PIM1 identified as a marker of poor prognosis.

Purpose of the Study:

  • To evaluate PIM kinase expression in NSCLC.
  • To investigate the efficacy of a novel PI3K/mTOR/PIM inhibitor, IBL-301, in preclinical NSCLC models.
  • To explore mechanisms of resistance to PI3K/mTOR inhibition and identify potential therapeutic strategies.

Main Methods:

  • Western blot analysis to confirm PIM kinase expression in NSCLC cell lines and patient-derived tumor tissues.
  • In vitro and in vivo studies using IBL-301 to assess its impact on protein levels, signaling pathways, and cytokine secretion.
  • Pathway arrays (IL-6/STAT3) and miRNA arrays to investigate mechanisms of drug resistance.

Main Results:

  • PIM1, PIM2, and PIM3 kinases are expressed in NSCLC cell lines; PIM1 is a poor prognostic marker.
  • IBL-301 reduced PIM1, c-Myc, pBAD, p4EBP1, and peIF4B protein levels in vitro.
  • IBL-301 inhibited MAP kinase, PI3K-Akt, and JAK/STAT pathways, and decreased MCP-1 secretion in tumor explants.
  • Apitolisib-resistant cells showed altered mRNA expression and were more sensitive to IBL-301.
  • A dysregulated miRNA signature associated with PI3K/mTOR resistance was identified.

Conclusions:

  • Co-targeting PIM kinase and PI3K-mTOR pathways presents a promising therapeutic strategy for NSCLC.
  • IBL-301 demonstrates potential as a novel agent for NSCLC treatment, overcoming resistance mechanisms.
  • Understanding miRNA regulation of PIM kinase and c-Myc is crucial for developing effective NSCLC therapies.
Keywords:
NSCLCPI3K-mTORPIM kinasebiomarkerc-Mycdrug resistancemiRNAtumor tissue explants

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