RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas.
Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice. These findings provide a rationale for the rapid implementation of genotype-specific targeted therapies using FAK inhibitors in patients with cancer.


CONCLUSIONS
Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes.
Department of Internal Medicine, Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Georgia
G
Konstantinidou
Giorgio
G
Ramadori
Francesca
F
Torti
Kim
K
Kangasniemi
Rachel E
RE
Ramirez
Yiran
Y
Cai
Carmen
C
Behrens
Michael T
MT
Dellinger
Rolf A
RA
Brekken
Ignacio I
II
Wistuba
Adriana
A
Heguy
Julie
J
Teruya-Feldstein
Pier Paolo
PP
Scaglioni
D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000077192:Adenocarcinoma of Lung; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020742:rhoA GTP-Binding Protein