Saraswat Aishwarya, Vemana Hari Priya, Dukhande Vikas, Patel Ketan
College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
Mol Ther Nucleic Acids. 2024 Jul 31;35(3):102292. doi: 10.1016/j.omtn.2024.102292. eCollection 2024 Sep 10.
Patients suffering from BRAF mutant melanoma have tumor recurrence within merely 7 months of treatment with a potent BRAF inhibitor (BRAFi) like vemurafenib. It has been proven that diverse molecular pathways driving BRAFi resistance converge to activation of c-Myc in melanoma. Therefore, we identified a novel combinatorial therapeutic strategy by targeting loss of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and upregulated BRD4 oncoprotein as Myc-dependent vulnerabilities of drug-resistant melanoma. Being promising therapeutic targets, we decided to concomitantly deliver PTEN plasmid and BRD4 targeted PROteolysis-TArgeting Chimera (ARV) to drug the "undruggable" c-Myc in BRAFi-resistant melanoma. Since PTEN plasmid and ARV are distinct in their physicochemical properties, we fabricated PTEN-plasmid loaded lipid nanoparticles (PL-NANO) and ARV-825-loaded nanoliposomes (AL-NANO) to yield a mean particle size of less than 100 nm and greater than 99% encapsulation efficiency for each therapeutic payload. Combination of PL-NANO and AL-NANO displayed synergistic tumor growth inhibition and substantial apoptosis in two-dimensional and three-dimensional models. Importantly, simultaneous delivery of PL-NANO and AL-NANO achieved significant upregulation of PTEN expression levels and degradation of BRD4 protein to ultimately downregulate c-Myc levels in BRAFi-resistant melanoma cells. Altogether, lipid nanocarriers delivering this novel lethal cocktail stands as one-of-a-kind gene therapy to target undruggable c-Myc oncogene in BRAFi-resistant melanoma.
患有BRAF突变型黑色素瘤的患者在使用维莫非尼等强效BRAF抑制剂（BRAFi）治疗仅7个月后就会出现肿瘤复发。事实证明，驱动BRAFi耐药的多种分子途径在黑色素瘤中都汇聚到c-Myc的激活上。因此，我们通过靶向10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）肿瘤抑制基因的缺失以及上调作为耐药性黑色素瘤中Myc依赖性脆弱点的BRD4癌蛋白，确定了一种新的联合治疗策略。作为有前景的治疗靶点，我们决定同时递送PTEN质粒和靶向BRD4的蛋白酶靶向嵌合体（ARV），以作用于BRAFi耐药黑色素瘤中 “不可成药” 的c-Myc。由于PTEN质粒和ARV在物理化学性质上不同，我们制备了负载PTEN质粒的脂质纳米颗粒（PL-NANO）和负载ARV-825的纳米脂质体（AL-NANO），以使每种治疗有效载荷的平均粒径小于100nm且包封效率大于99%。PL-NANO和AL-NANO的组合在二维和三维模型中显示出协同的肿瘤生长抑制和大量凋亡。重要的是，同时递送PL-NANO和AL-NANO可使BRAFi耐药黑色素瘤细胞中PTEN表达水平显著上调和BRD4蛋白降解，最终下调c-Myc水平。总之，递送这种新型致命组合的脂质纳米载体是一种独特的基因疗法，可靶向BRAFi耐药黑色素瘤中不可成药的c-Myc癌基因。
