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3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

Ismail M Meraz1, Mourad Majidi2, Bingliang Fang2

  • 1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. imeraz@mdanderson.org.

Communications Biology
|May 11, 2023
PubMed

Insights

Acquired resistance to osimertinib in non-small cell lung cancer (NSCLC) is driven by 3-phosphoinositide-dependent kinase 1 (PDK1). Inhibiting PDK1 re-sensitizes resistant NSCLC tumors to osimertinib by targeting PI3K/Akt/mTOR and YAP pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Resistance Mechanisms

Background:

  • Acquired resistance to targeted therapies like osimertinib is a major challenge in non-small cell lung cancer (NSCLC) treatment.
  • Understanding the molecular mechanisms underlying this resistance is crucial for developing effective therapeutic strategies.

Purpose of the Study:

  • To investigate the mechanisms of acquired resistance to osimertinib in NSCLC.
  • To identify potential therapeutic targets for overcoming osimertinib resistance.

Main Methods:

  • Utilized osimertinib-sensitive and resistant NSCLC cell lines (NCI-H1975) in humanized and non-humanized mouse models.
  • Employed CRISPR gene knockout and pharmacological inhibition (BX795) to target 3-phosphoinositide-dependent kinase 1 (PDK1).
  • Analyzed signaling pathways including PI3K/Akt/mTOR and YAP, and assessed cell cycle progression.

Main Results:

  • Resistant NSCLC tumors exhibited aggressive regrowth and reduced sensitivity to osimertinib, without new EGFR mutations.
  • 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a key driver of osimertinib resistance.
  • Inhibition of PDK1, via genetic knockout or BX795, sensitized resistant cells and tumors, including patient-derived xenografts (PDX).
  • PDK1 inhibition dysregulated PI3K/Akt/mTOR, induced G1 cell cycle arrest, and reduced YAP nuclear translocation.
  • Elevated PDK1 expression and its association with YAP correlated with progressive disease in patients post-osimertinib treatment.

Conclusions:

  • PDK1 is a critical upstream regulator of both PI3K/Akt/mTOR and YAP pathways, driving acquired osimertinib resistance in NSCLC.
  • Targeting PDK1 represents a promising strategy to re-sensitize NSCLC tumors to osimertinib.
  • PDK1 inhibition offers a potential therapeutic approach to overcome acquired resistance in NSCLC patients.

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