RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas

Georgia Konstantinidou, Giorgio Ramadori, Francesca Torti, Kim Kangasniemi, Rachel E. Ramirez, Yiran Cai, Carmen Behrens, Michael T. Dellinger, Rolf A. Brekken, Ignacio I. Wistuba, Adriana Heguy, Julie Teruya-Feldstein, Pier Paolo Scaglioni

Research output: Contribution to journalArticlepeer-review

89 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)444-457
Number of pages14
JournalCancer discovery
Issue number4
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Oncology


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