Signal therapy for RAS-induced cancers in combination of AG 879 and PP1, specific inhibitors for ErbB2 and Src family kinases, that block PAK activation.

摘要: BACKGROUND: Both EGF family ligands and ErbB receptor kinases act upstream of RAS to induce mitogenesis normal cells, such as NIH 3T3 fibroblasts. However, oncogenically mutated RAS, v-Ha-RAS is constitutively activated therefore no longer requires these or receptors for its activation. Nevertheless, it up-regulates the expression ligands. To understand biologic significance RAS-induced up-regulation in both PAK activation malignant transformation, we have conducted following studies, based on previous observations that (1) N-terminal SH3 domain PIX selectively binds a Pro-rich 18 amino acids PAKs, CDC42/Rac-dependent Ser/Thr kinase family, (2) this specific interaction essential membrane ruffling RESULTS: Using four distinct, cell-permeable, highly inhibitors, namely WR-PAK18, which blocks PAK-PIX interaction; AG 1478, inhibits ErbB1 activity; 825 879, ErbB2 activity, demonstrate v-Ha-RAS-induced transformation; not only but also ErbB2, are through two independent autocrine pathways PIX/Rac/CDC42-dependent transformation vitro; (3) combination 879 Src kinase-specific inhibitor PP1 suppresses almost completely growth sarcomas nude mice. CONCLUSION: These findings change our conventional view role RAS-inducible (serving activators) suggest new avenue treatment RAS-associated cancers by inhibitors ERbB, Src, kinases.