The present invention includes compositions and methods for making and using a bifunctional shRNAs capable of reducing an expression of a K-ras gene, eg., a mutated K-ras gene, wherein at least one target site sequence of the bifunctional RNA molecule is located within the K-ras gene and wherein the bifunctional RNA molecule is capable of activating a cleavage-dependent and a cleavage-independent RNA-induced silencing complex for reducing the expression level of K-ras.本發明包括一種製造及使用能夠減少K-ras基因(例如突變K-ras基因)表現之雙功能性shRNA之組合物及方法,其中該雙功能性RNA分子之至少一個靶位點序列係位於該K-ras基因內,且其中該雙功能性RNA分子能夠活化裂解依賴型及非裂解依賴型RNA誘導之沉默複合物,以減少K-ras之表現量。