Molecular therapeutic strategy combining idelalisib and srpin340 to treat advance solid tumors

Abstract

PI3Kδ implicates hematologic cancers and solid tumors. Alternative splicing is a post-transcriptional process for acquiring proteomic diversity in eukaryotic cells. Emerging evidence highlights the involvement of aberrant mRNA splicing in cancer development/progression. PI3Kδ-L and PI3Kδ-S are overexpressed in advanced solid tumors, such as prostate, breast, colon, lung and pancreatic cancers. Differential PI3Kδ and PI3Kδ-S expression profiles were identified in a panel of solid tumor cells. PI3Kδ inhibitor Idelalisib and SRPK1/2 inhibitor SRPIN340 were employed to assess their efficacies on inhibiting the PI3Kδ-expressing solid tumors. Idelalisib effectively inhibits PI3Kδ-L and its downstream signaling. Idelalisib fails to inhibit PI3Kδ-S activity and its downstream signaling. SRPIN340 reverses the aberrant mRNA splicing, thereby inhibiting the downstream AKT/mTOR signaling. In vitro functional assays further demonstrate that a combination of Idelalisib and SRPIN340 achieve a synergistic drug effect, with drastically reduced cell viabilities/growths of tumor spheroids, in inhibiting the advanced tumor cells.

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