Editors' ChoiceCancer

Anticancer Cocktails

Sci. Signal.  14 Oct 2014:
Vol. 7, Issue 347, pp. ec284
DOI: 10.1126/scisignal.aaa0425

Disrupting the signaling pathways on which cancer cells rely for proliferation and survival can reduce the growth and spread of tumors. However, targeting a single pathway component often leads to only a temporary reduction in tumor growth due to the development of resistance. Combinatorial treatment has emerged as an effective strategy for reducing the emergence of drug resistance. Members of the RAS family of small GTPases, such as KRAS, activate a kinase cascade consisting of RAF, MEK, and ERK, and dysregulated RAS activity is associated with many types of cancer. Yuan et al. reported that nanoparticles containing relatively low doses of small interfering RNAs (siRNAs) targeting KRAS or its downstream effectors reduced tumor growth in a KRAS-driven colorectal cancer xenograft model. Low doses (as little as 0.5 nmol/L) of siRNAs targeting KRAS specifically reduced the abundance of KRAS without detectable off-target effects when transfected into cultured mouse embryonic fibroblasts and cultured osteosarcoma cells. Knocking down KRAS alone or knocking down all three RAF isoforms (ARAF, BRAF, and CRAF) simultaneously, but not individually, in KRAS-driven cultured colorectal cancer cells reduced cell viability, stimulated apoptosis, and decreased the abundance of phosphorylated ERK (pERK) with similar effectiveness. Intravenous delivery of a nanoparticle-packaged siRNA targeting KRAS inhibited the growth of KRAS-driven colorectal xenografts; the tumors regressed during the first week of treatment and thereafter grew more slowly than in the untreated animals. Tumors resected from treated mice had reduced abundance of KRAS, pERK, and pCRAF, and increased abundance of the cell cycle inhibitor p21. Treating mice with nanoparticles containing siRNAs targeting all three RAF isoforms also inhibited tumor growth. Phosphoinositide 3-kinase (PI3K) can be activated both RAS-dependently and RAS-independently and is required for the survival of many types of tumors. Treating mice harboring KRAS-driven colorectal cancer xenografts with nanoparticles containing siRNAs that target both KRAS and a catalytic subunit of PI3K inhibited tumor growth better than KRAS-siRNA treatment alone. Furthermore, in vitro experiments showed that transfecting cocktails containing as many as seven different siRNAs effectively reduced the abundance of the seven target proteins, implying the possibility of designing treatment strategies targeting different combinations of proteins for different types of tumors.

T. L. Yuan, C. Fellmann, C.-S. Lee, C. D. Ritchie, V. Thapar, L. C. Lee, D. J. Hsu, D. Grace, J. O. Carver, J. Zuber, J. Luo, F. McCormick, S. W. Lowe, Development of siRNA payloads to target KRAS-mutant cancer. Cancer Discov. 4, 1182–1197 (2014). [PubMed]