Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma
Melissa Gilbert-Ross, … , Wei Zhou, Adam I. Marcus
Melissa Gilbert-Ross, … , Wei Zhou, Adam I. Marcus
Published March 9, 2017
Citation Information: JCI Insight. 2017;2(5):e90487. https://doi.org/10.1172/jci.insight.90487.
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Research Article Cell biology Oncology

Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma

Abstract

Loss of LKB1 activity is prevalent in KRAS mutant lung adenocarcinoma and promotes aggressive and treatment-resistant tumors. Previous studies have shown that LKB1 is a negative regulator of the focal adhesion kinase (FAK), but in vivo studies testing the efficacy of FAK inhibition in LKB1 mutant cancers are lacking. Here, we took a pharmacologic approach to show that FAK inhibition is an effective early-treatment strategy for this high-risk molecular subtype. We established a lenti-Cre–induced Kras and Lkb1 mutant genetically engineered mouse model (KLLenti) that develops 100% lung adenocarcinoma and showed that high spatiotemporal FAK activation occurs in collective invasive cells that are surrounded by high levels of collagen. Modeling invasion in 3D, loss of Lkb1, but not p53, was sufficient to drive collective invasion and collagen alignment that was highly sensitive to FAK inhibition. Treatment of early, stage-matched KLLenti tumors with FAK inhibitor monotherapy resulted in a striking effect on tumor progression, invasion, and tumor-associated collagen. Chronic treatment extended survival and impeded local lymph node spread. Lastly, we identified focally upregulated FAK and collagen-associated collective invasion in KRAS and LKB1 comutated human lung adenocarcinoma patients. Our results suggest that patients with LKB1 mutant tumors should be stratified for early treatment with FAK inhibitors.

Authors

Melissa Gilbert-Ross, Jessica Konen, Junghui Koo, John Shupe, Brian S. Robinson, Walter Guy Wiles IV, Chunzi Huang, W. David Martin, Madhusmita Behera, Geoffrey H. Smith, Charles E. Hill, Michael R. Rossi, Gabriel L. Sica, Manali Rupji, Zhengjia Chen, Jeanne Kowalski, Andrea L. Kasinski, Suresh S. Ramalingam, Haian Fu, Fadlo R. Khuri, Wei Zhou, Adam I. Marcus

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Figure 4

KRAS and LKB1 comutated human lung adenocarcinoma exhibits focal upregulation of pYFAK and collagen-associated collective invasion packs (CIPs).

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KRAS and LKB1 comutated human lung adenocarcinoma exhibits focal upregu...
(A) Representative confocal image (left) of E-Cadherin (green) and SHG image (right) of collagen (white) in human KRAS mutant lung adenocarcinoma. The field imaged by confocal microscopy was subsequently reimaged for collagen using SHG (200×) (B) Representative confocal images (left column) and SHG images of E-Cadherin (green) and collagen (white) of 2 independent fields from a KRAS and LKB1 mutant human primary lung adenocarcinoma (top and middle panels). As in A, fields imaged by confocal microscopy were subsequently reimaged with SHG to detect collagen. Confocal imaging of E-Cadherin (left) and an adjacent section stained for pYFAK (right) is pictured in the bottom panel. Red arrows mark CIPs present in both sections that are E-Cadherin– and pYFAK-positive. All panels imaged at 200×. (C) Quantitation of collagen density by mean SHG signal intensity. Each data point represents an independent field, and 2 independent fields were imaged per patient with n = 6 KRAS and n = 6 KRAS and LKB1 mutant patients. Data are presented as mean ± SD. Two-tailed t test; *P < 0.05. (D) Representative images of pYFAK397 IHC from 3 independent patient samples per indicated genotype (representative images from a total of n = 7 KRAS and n = 6 KRAS and LKB1 mutant patients samples [15 total patients]).