Abstract: Compositions and methods for treating cancers are provided which comprise administering a combination of antineoplastic agents, wherein the combination comprises protein kinase inhibitor, anthracycline, nucleoside analog, apoptosis-inducing molecular therapeutic or alkylating agent chemotherapeutics and one or more nucleic acid molecules capable of down-regulating expression of at least one splice variant of the IG20 gene, and wherein not all splice variants of the IG20 gene are down-regulated. Preferably, the splice variant of the IG20 gene is a MADD splice variant and the nucleic acid molecules are siRNA, shRNA and antisense oligonucleotides which comprise a nucleic acid sequence complementary to a nucleic acid sequence of exon 13L of the MADD splice variant or to an mRNA transcript of exon 13L of the MADD splice variant.