Inhibition of EGFR signaling downregulates K-RAS mutated activity

KRAS mutations are the ost abundand driver mutations found in lung adenocarcinoma patients. Unfortunately, there are no clinical approved inhibitors available, to directly target mutant forms of KRAS. The aim of the study was to unravel the impact of upstream Egfr activation in signaling of mutated K-ras. We found that upregulation of G12D mutant Kras induced genes was significantly impaired when Egfr was knocked out. Our data suggests that signaling of mutant Kras depends on upstream activation. This finding may be exploited therapeutically by targeting EGFR in KRAS mutant patients. Overall design: We isolated mouse alveolar type II cells and induced the Kras G12D mutation, with and without concomitant Egfr knockout, in vitro. Cells lysates were analyzed 5 days following transgene induction.

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Mohrherr J, Haber M, Breitenecker K, Aigner P, Moritsch S, Voronin V, Eferl R, Moriggl R, Stoiber D, Győrffy B, Brcic L, László V, Döme B, Moldvay J, Dezső K, Bilban M, Popper H, Moll HP, Casanova E