Related Experiment Video

Updated: Jul 13, 2025

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

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Differential network analysis of ROS1 inhibitors reveals lorlatinib polypharmacology through co-targeting PYK2

Yi Liao1, Lily L Remsing Rix1, Xueli Li1

  • 1Department of Drug Discovery, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA.

Cell Chemical Biology
|October 17, 2023
PubMed

Insights

Lorlatinib shows superior potency against ROS1-positive lung cancer by uniquely inhibiting focal adhesion signaling. This tyrosine kinase inhibitor (TKI) targets both ROS1 and PYK2, suggesting novel combination therapies for lung cancer.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Multiple tyrosine kinase inhibitors (TKIs) exist for similar indications, but their comparative efficacy and off-target effects are often unclear.
  • Unrecognized targets cooperating with intended targets can influence TKI efficacy in cancer treatment.

Purpose of the Study:

  • To compare the cellular potency of various ROS1 TKIs against ROS1-fusion-positive lung cancer.
  • To elucidate the underlying mechanisms of differential TKI efficacy and identify potential drug combination strategies.

Main Methods:

  • Comparative analysis of ROS1 TKIs for cell viability, ROS1 autophosphorylation, and kinase activity.
  • Quantitative chemical and phosphoproteomics coupled with differential network analysis.
  • Functional validation via pharmacological probes, RNA interference, and CRISPR-Cas9 knockout.

Main Results:

  • Lorlatinib demonstrated disproportionately higher cellular potency compared to other ROS1 TKIs.
  • Lorlatinib uniquely impacted focal adhesion signaling, revealing a polypharmacology mechanism.
  • Dual targeting of ROS1 and PYK2 by lorlatinib was identified, involving a complex with SRC.
  • Combining lorlatinib with SRC inhibitors showed significant synergistic effects.

Conclusions:

  • Systems pharmacology and network analysis can dissect complex polypharmacology mechanisms of TKIs.
  • Lorlatinib's dual targeting of ROS1 and PYK2 offers a rationale for combination therapy in lung cancer.
  • This approach enables the design of rational drug combinations for improved cancer treatment outcomes.
Keywords:
LorlatinibPYK2ROS1SRCchemoproteomicsnetwork analysisnon-small cell lung cancerphosphoproteomicspolypharmacologysynergy

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