Kim, Min Ju Lee, So Jin Ryu, Ju Hee Kim, Sun Hwa Kwon, Ick Chan Roberts, Thomas M. 2024-01-19T18:04:43Z 2024-01-19T18:04:43Z 2021-09-04 2020-02 0168-3659 https://pubs.kist.re.kr/handle/201004/119029 The phosphoinositide 3-kinase (PI3K) and RAS signaling pathways are frequently co-activated and altered during oncogenesis. Owing to their regulatory cross-talk, the early attempts of targeting only one pathway have mostly ended up promoting the development of drug resistance. Here, we propose using small interfering RNA (siRNA) therapeutics to directly target the undruggable KRAS (siKRAS) in combination with the pan-PI3K inhibitor GDC-0941 (GDC) to simultaneously block both PI3K and RAS signaling, thereby exerting synergistic anti-tumor effects on ovarian cancers with PTEN deficiency and KRAS(G12D) mutation. For successful delivery of siKRAS, tGC/psi-nanoparticle formulation of polymerized siRNA and thiol-modified glycol chitosan nanoparticle-was used for KRAS specific inhibition in vitro and in vivo. GDC or siKRAS monotherapy each impede downstream signaling, leading to some delay in cell proliferation and migration. When combined, however, they engender much higher inhibition of PI3K signaling and stimulation of apoptosis in an ovarian allograft model compared to monotherapies. Our results show the feasibility of developing new combination strategies for the management of multiple oncogenic mutations activating PI3K and RAS signaling. English ELSEVIER CELLULAR UPTAKE MEK INHIBITORS SIRNA DELIVERY CROSS-TALK RESISTANCE PATHWAY RAS ISOFORM NANOPARTICLE P110-ALPHA Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment Article 10.1016/j.jconrel.2019.12.019 1 JOURNAL OF CONTROLLED RELEASE, v.318, pp.98 - 108 JOURNAL OF CONTROLLED RELEASE 318 98 108 scie scopus 000512735400009 2-s2.0-85076635351 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article CELLULAR UPTAKE MEK INHIBITORS SIRNA DELIVERY CROSS-TALK RESISTANCE PATHWAY RAS ISOFORM NANOPARTICLE P110-ALPHA PI3K Combination therapy KRAS siRNA Ovarian Cancer