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Related Concept Videos

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Related Experiment Video

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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
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Resistance Profile and Structural Modeling of Next-Generation ROS1 Tyrosine Kinase Inhibitors.

Clare Keddy1,2, Pushkar Shinde3, Kristen Jones1,2

  • 1Division of Pediatric Hematology/Oncology, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.

Molecular Cancer Therapeutics
|December 15, 2021
PubMed
Summary
This summary is machine-generated.

Acquired resistance to ROS1 inhibitors like entrectinib limits treatment durability in non-small cell lung cancer (NSCLC). This study identified specific ROS1 mutations conferring resistance, suggesting new therapeutic strategies involving type II inhibitors or inhibitor cycling.

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A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
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Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • ROS1 fusions are oncogenic drivers in various cancers, particularly non-small cell lung cancer (NSCLC).
  • Targeted tyrosine kinase inhibitors (TKIs) show efficacy against ROS1-driven cancers, but acquired resistance limits long-term clinical benefit.
  • Entrectinib, lorlatinib, and repotrectinib are key TKIs used or investigated for ROS1-positive NSCLC.

Purpose of the Study:

  • To identify novel resistance mutations to entrectinib, lorlatinib, and repotrectinib in ROS1 fusion-driven cancers.
  • To understand the mechanisms of resistance to different classes of ROS1 inhibitors.
  • To inform the development of next-generation inhibitors or treatment strategies to overcome resistance.

Main Methods:

  • Utilized an unbiased forward mutagenesis screen in Ba/F3 cells engineered with CD74-ROS1 and EZR-ROS1 fusions.
  • Exposed cells to entrectinib, lorlatinib, and repotrectinib to select for resistant clones.
  • Characterized identified mutations (e.g., ROS1F2004C, ROS1G2032R, ROS1L2086F) through cell-based assays and modeling.

Main Results:

  • Identified ROS1F2004C as a recurrent mutation conferring resistance to entrectinib.
  • Discovered ROS1G2032R in clones resistant to both entrectinib and lorlatinib.
  • Demonstrated that entrectinib acts as a dual type I/II inhibitor, susceptible to both resistance mutation types.
  • Found ROS1L2086F confers broad resistance to type I inhibitors but retains sensitivity to type II inhibitors.
  • Showed ROS1F2004C/I/V mutations confer resistance to type I (entrectinib, crizotinib) and type II (cabozantinib) inhibitors but remain sensitive to type I macrocyclic inhibitors.

Conclusions:

  • Specific kinase domain mutations in ROS1 confer resistance to clinically relevant TKIs.
  • Understanding inhibitor binding modes (type I vs. type II) is crucial for predicting resistance patterns.
  • Developing selective type II ROS1 inhibitors or employing inhibitor cycling strategies may enhance treatment durability in ROS1-driven NSCLC.