RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas Journal Article
| Authors: | Konstantinidou, G.; Ramadori, G.; Torti, F.; Kangasniemi, K.; Ramirez, R. E.; Cai, Y.; Behrens, C.; Dellinger, M. T.; Brekken, R. A.; Wistuba, I. I.; Heguy, A.; Teruya-Feldstein, J.; Scaglioni, P. P. |
| Article Title: | RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas |
| Abstract: | 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. Significance: 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. © 2013 American Association for Cancer Research. |
| Keywords: | signal transduction; mitogen activated protein kinase; controlled study; protein expression; unclassified drug; gene mutation; gene sequence; human cell; placebo; nonhuman; polymerase chain reaction; adenocarcinoma; ki 67 antigen; animal cell; mouse; animals; mice; cell death; gene amplification; mitogen activated protein kinase kinase 1; mitogen activated protein kinase kinase 2; carcinoma, non-small-cell lung; lung neoplasms; animal experiment; animal model; small interfering rna; rna interference; in vivo study; in vitro study; tumor regression; xenograft model antitumor assays; cell line, tumor; protein p53; histology; mice, transgenic; protein kinase inhibitors; lung tumor; cancer inhibition; lung adenocarcinoma; cell culture; mice, nude; cancer cell; cancer infiltration; immunoblotting; extracellular signal-regulated map kinases; rhoa guanine nucleotide binding protein; protein deficiency; gene silencing; arf protein; cyclin dependent kinase inhibitor 2a; genes, ras; doxycycline; focal adhesion kinase; sodium chloride; protein inhibitor; mutant; focal adhesion protein-tyrosine kinases; intracellular signaling; selumetinib; rac1 protein; rhoa gtp-binding protein; fak14 inhibitor; pf 562271 |
| Journal Title: | Cancer Discovery |
| Volume: | 3 |
| Issue: | 4 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-04-01 |
| Start Page: | 444 |
| End Page: | 457 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-12-0388 |
| PROVIDER: | scopus |
| PMCID: | PMC3625467 |
| PUBMED: | 23358651 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 3 June 2013" - "Source: Scopus" |
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