Mutant KRAS is a druggable target for pancreatic cancer

Elina Zorde Khvalevsky, Racheli Gabai, Itzhak Haim Rachmut, Elad Horwitz, Zivia Brunschwig, Ariel Orbach, Adva Shemi, Talia Golan, Abraham J. Domb, Eylon Yavin, Hilla Giladi, Ludmila Rivkin, Alina Simerzin, Rami Eliakim, Abed Khalaileh, Ayala Hubert, Maor Lahav, Yael Kopelman, Eran Goldin, Alan DancourYael Hants, Sagit Arbel-Alon, Rinat Abramovitch, Amotz Shemi, Eithan Galun*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.

Original languageEnglish
Pages (from-to)20723-20728
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number51
DOIs
StatePublished - 17 Dec 2013

Keywords

  • Gene therapy
  • Targeted therapy

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