KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.He...KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.Herein,we present a novel self-assembled nanoparticle(HA-TPP/A)that are functionalized nano-carrier hyaluronic acid(HA)-TPP conjugate(HA-TPP)to degrade mutant p53 proteins(mutp53)and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways.The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria.Furthermore,these nanoparticles abrogated the gain-of-function(GOF)phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing,thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation.The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model,particularly in KRAS-TP53 double mutant expressing cancer cells,compared with single drug and combined free drug groups.Notably,HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53,providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.展开更多
基金supported by the National Key Research and Development Plan(2022YFC3401000)National Natural Science Foundation of China(81871994,82022037,T2222014 and 32071398)+2 种基金Guangdong Provincial Natural Science Foundation(2019B151502063)Guangdong Basic and Applied Basic Research Foundation(2021B1515230009)Key Research and Development Plan of Guangdong Province(2020B0101030006,2020B1515120096 and 2022B0202010002).
文摘KRAS-TP53 co-mutation is strongly associated with poor prognosis and high malignancy in gastrointestinal cancers.Therefore,a novel approach to oncotherapy may lie in combination therapy targeting both KRAS and TP53.Herein,we present a novel self-assembled nanoparticle(HA-TPP/A)that are functionalized nano-carrier hyaluronic acid(HA)-TPP conjugate(HA-TPP)to degrade mutant p53 proteins(mutp53)and co-deliver AMG510 for treating KRAS-TP53 co-alteration of gastrointestinal cancers by inhibiting the mutant KRAS and mutp53 signaling pathways.The HA-TPP/A nanoparticles led to ubiquitination-dependent proteasomal degradation of mutp53 by targeting damage to mitochondria.Furthermore,these nanoparticles abrogated the gain-of-function(GOF)phenotypes of mutp53 and increased sensitivity to AMG510-induced cell killing,thereby reducing cell proliferation and migration in gastrointestinal cancer with KRAS-TP53 co-mutation.The co-loaded HA-TPP/A nanoparticles demonstrated remarkable therapeutic efficacy in a tumor-bearing mouse model,particularly in KRAS-TP53 double mutant expressing cancer cells,compared with single drug and combined free drug groups.Notably,HA-TPP/A is the first reported nanoparticle with an ability to co-target KRAS-TP53,providing a promising approach for therapy in highly malignant gastrointestinal tumors and potentially expanding clinical indications for AMG510 targeted therapies in gastrointestinal tumors.
