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Published on: May 22, 2020
Engineered a dual-targeting HA-TPP/A nanoparticle for combination therapy against KRAS-TP53 co-mutation in
Yong Mei1, Xiaohua Qin2, Zhenyu Yang2
1Department of Gastrointestinal Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, 510080, China.
Abstract:
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.
Insights
A new nanoparticle therapy targets both KRAS and mutant p53 (mutp53) in gastrointestinal cancers. This approach degrades mutp53 and delivers AMG510, showing promise for treating aggressive tumors.
Area of Science:
- Oncology
- Nanomedicine
- Molecular Biology
Background:
- KRAS-TP53 co-mutation is linked to poor prognosis in gastrointestinal cancers.
- Targeting both KRAS and TP53 mutations offers a novel therapeutic strategy.
Purpose of the Study:
- To develop and evaluate a novel nanoparticle (HA-TPP/A) for co-targeting KRAS and mutant p53 (mutp53) in gastrointestinal cancers.
- To assess the efficacy of HA-TPP/A in inhibiting oncogenic signaling and reducing tumor progression.
Main Methods:
- Self-assembled nanoparticles (HA-TPP/A) functionalized with hyaluronic acid-TPP conjugate were synthesized.
- Nanoparticles co-delivered AMG510 and induced mutp53 degradation via ubiquitination-dependent proteasomal pathways.
- In vitro and in vivo studies evaluated therapeutic efficacy in KRAS-TP53 co-mutant models.
Main Results:
- HA-TPP/A nanoparticles induced mutp53 degradation and abrogated its gain-of-function phenotypes.
- These nanoparticles enhanced sensitivity to AMG510, reducing cancer cell proliferation and migration.
- Significant therapeutic efficacy was observed in a tumor-bearing mouse model, outperforming single-agent treatments.
Conclusions:
- HA-TPP/A represents the first nanoparticle capable of co-targeting KRAS and TP53 mutations.
- This novel approach shows promise for treating highly malignant gastrointestinal tumors with KRAS-TP53 co-alterations.
- The findings may expand clinical applications for AMG510 in gastrointestinal oncology.
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