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Combination of KRAS gene silencing and PI3K inhibition for ovarian cancer treatment.
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-12-12 , DOI: 10.1016/j.jconrel.2019.12.019 Min Ju Kim 1 , So Jin Lee 2 , Ju Hee Ryu 2 , Sun Hwa Kim 3 , Ick Chan Kwon 1 , Thomas M Roberts 4
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2019-12-12 , DOI: 10.1016/j.jconrel.2019.12.019 Min Ju Kim 1 , So Jin Lee 2 , Ju Hee Ryu 2 , Sun Hwa Kim 3 , Ick Chan Kwon 1 , Thomas M Roberts 4
Affiliation
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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 KRASG12D 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.
中文翻译：
结合KRAS基因沉默和PI3K抑制治疗卵巢癌。
磷酸肌醇3-激酶（PI3K）和RAS信号通路在致癌过程中经常被共同激活和改变。由于它们之间的调节性相互干扰，仅针对一种途径的早期尝试大多以促进耐药性的发展而告终。在这里，我们建议使用小干扰RNA（siRNA）治疗剂与泛PI3K抑制剂GDC-0941（GDC）结合直接靶向不可消耗的KRAS（siKRAS），以同时阻断PI3K和RAS信号传导，从而发挥协同抗肿瘤作用对PTEN缺乏和KRASG12D突变的卵巢癌的影响。为了成功递送siKRAS，将聚合的siRNA和巯基修饰的乙二醇壳聚糖纳米颗粒的tGC / psi-纳米颗粒制剂用于体外和体内KRAS特异性抑制。GDC或siKRAS单一疗法均会阻碍下游信号传导，从而导致细胞增殖和迁移有所延迟。但是，与单一疗法相比，当组合使用时，它们在卵巢同种异体移植模型中对PI3K信号的抑制作用和对细胞凋亡的刺激作用更高。我们的结果表明开发新的组合策略以管理激活PI3K和RAS信号转导的多个致癌突变的可行性。
更新日期：2019-12-13
中文翻译：
结合KRAS基因沉默和PI3K抑制治疗卵巢癌。
磷酸肌醇3-激酶（PI3K）和RAS信号通路在致癌过程中经常被共同激活和改变。由于它们之间的调节性相互干扰，仅针对一种途径的早期尝试大多以促进耐药性的发展而告终。在这里，我们建议使用小干扰RNA（siRNA）治疗剂与泛PI3K抑制剂GDC-0941（GDC）结合直接靶向不可消耗的KRAS（siKRAS），以同时阻断PI3K和RAS信号传导，从而发挥协同抗肿瘤作用对PTEN缺乏和KRASG12D突变的卵巢癌的影响。为了成功递送siKRAS，将聚合的siRNA和巯基修饰的乙二醇壳聚糖纳米颗粒的tGC / psi-纳米颗粒制剂用于体外和体内KRAS特异性抑制。GDC或siKRAS单一疗法均会阻碍下游信号传导，从而导致细胞增殖和迁移有所延迟。但是，与单一疗法相比，当组合使用时，它们在卵巢同种异体移植模型中对PI3K信号的抑制作用和对细胞凋亡的刺激作用更高。我们的结果表明开发新的组合策略以管理激活PI3K和RAS信号转导的多个致癌突变的可行性。
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