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Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma

Melissa Gilbert-Ross1,2, Jessica Konen1,2, Junghui Koo1,2

  • 1Department of Hematology and Medical Oncology, Emory University School of Medicine.

JCI Insight
|March 15, 2017
PubMed

Insights

Loss of LKB1 activity in KRAS-mutant lung cancer drives aggressive tumors. FAK inhibition effectively treats these tumors by reducing invasion and collagen, improving survival.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Loss of Liver Kinase B1 (LKB1) activity is common in KRAS-mutant lung adenocarcinoma, contributing to aggressive and treatment-resistant tumors.
  • LKB1 negatively regulates focal adhesion kinase (FAK), but in vivo efficacy of FAK inhibition in LKB1-mutant cancers remains understudied.

Purpose of the Study:

  • To investigate the efficacy of FAK inhibition as an early-treatment strategy for LKB1-inactivated KRAS-mutant lung adenocarcinoma.
  • To elucidate the role of FAK activation in tumor invasion and collagen remodeling in LKB1-deficient lung cancer.

Main Methods:

  • Development of a Kras and Lkb1 mutant genetically engineered mouse model (KL_Lenti) for lung adenocarcinoma.
  • Pharmacologic inhibition of FAK in established KL_Lenti tumors and 3D invasion models.
  • Analysis of tumor progression, invasion, collagen content, and lymph node metastasis.
  • Identification of FAK and collagen-associated invasion in human lung adenocarcinoma patient samples.

Main Results:

  • KL_Lenti mice developed 100% lung adenocarcinoma with high FAK activation in collective invasive cells and aligned collagen.
  • Loss of LKB1, but not p53, drove collective invasion sensitive to FAK inhibition.
  • FAK inhibitor monotherapy significantly reduced tumor progression, invasion, and associated collagen in early-stage KL_Lenti tumors.
  • Chronic FAK inhibition extended survival and reduced lymph node spread.
  • Human KRAS/LKB1 co-mutant lung adenocarcinomas showed upregulated FAK and collagen-associated collective invasion.

Conclusions:

  • FAK inhibition is a promising early-treatment strategy for LKB1-mutant lung adenocarcinoma.
  • Targeting FAK may counteract tumor invasion and metastasis driven by LKB1 loss.
  • Stratification of LKB1-mutant lung cancer patients for early FAK inhibitor treatment is warranted.

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